Nanotherapy for acute pancreatitis: a systematic review of experimental strategies and mechanisms of action.

The targeting (directed transport) of nanoparticles can be classified into passive and active modes. Passive targeting relies on the inherent physiological characteristics of inflamed tissues (e.g., the enhanced permeability and retention (EPR) effect), whereas active targeting involves the use of specific ligands or biomimetic coatings to enable the selective delivery of nanomaterials to particular cells, receptors, or the inflammatory microenvironment. Passive targeting relies on the principle that, during inflammation, blood vessels become more permeable and lymphatic drainage is impaired. In the context of AP, this allows nanoparticles of specific sizes and physicochemical properties to accumulate passively in inflamed pancreatic tissues without requiring specific ligands. The classical mechanism underlying this process is the enhanced permeability and retention (EPR) effect, which is well established in oncology but is also applicable to acute inflammation. Through this mechanism, nanomaterials traverse widened inter-endothelial gaps in damaged vasculature and are retained in edematous tissues with compromised lymphatic clearance. Experimental studies have confirmed the effectiveness of passive accumulation of nanodrugs in the pancreas. For example, polyamidoamine (PAMAM) dendrimers, administered without any active targeting ligands, significantly reduce macrophage infiltration and inflammation in pancreatic tissues in AP models [ 69 ]. These findings demonstrate that such nanoparticles can passively reach inflamed areas and exert therapeutic effects through their inherent properties. Similarly, nanoliposomes loaded with caffeic acid phenethyl ester (CAPE) exhibit significant anti-inflammatory effects in AP models by modulating the Nrf2 and NF-κB pathways despite the lack of surface-targeting ligands [ 66 ]. The accumulation of these liposomes in pancreatic tissue is driven solely by passive targeting, resulting in reduced oxidative stress and inflammation. Passively targeted nanoparticles often function as “nanopharmaceuticals” with intrinsic antioxidant and anti-inflammatory activities. Cerium oxide nanoparticles (CeO 2 , or nanoceria) are well-known nanozymes that mimic the activity of SOD. In AP, nanoceria are systemically distributed throughout the body but preferentially accumulate in the pancreas owing to the EPR effect, where they scavenge excessive ROS, thereby alleviating oxidative stress and inflammation. Khurana et al. demonstrated that nanoceria effectively inhibit the progression of pancreatitis by mimicking antioxidant enzymes and suppressing NF-κB activation without requiring active targeting moieties [ 48 ]. Ultrasmall inorganic nanoparticles also exemplify the benefits of passive targeting. Jin et al. reported that polyvinylpyrrolidone-coated iridium nanocomplexes, which are only a few nanometers in size, can passively accumulate in the inflamed pancreas via the EPR effect [ 44 ]. These nanoparticles provide local antioxidant and anti-inflammatory actions by penetrating the compromised microvasculature and reducing inflammatory cytokine levels. Similarly, molybdenum diselenide nanosheets (MoSe 2 @PVP), which exhibit catalase- and peroxidase-like activities, also accumulate passively in inflamed pancreatic tissues and scavenge ROS and reactive nitrogen species (RNS) without any targeting ligands [ 68 ]. A major advantage of passive targeting is its simplicity in terms of nanomaterial design. The optimal size, shape, surface chemistry, and circulation time can be tuned to maximize passive accumulation in the pancreas. Many natural compounds with poor bioavailability have been successfully delivered to inflamed pancreatic tissues through passive mechanisms, thereby significantly increasing their therapeutic efficacy. For example, nano-curcumin (curcumin-loaded nanoparticles) alleviated pancreatic injury in AP by suppressing TLR4/NF-κB signaling, even though the carrier lacked active targeting functionality [ 65 ]. Tetrahedral framework nucleic acids (tFNAs), which are four-stranded DNA nanostructures, passively accumulate in the pancreas following systemic administration in mice with severe AP, where they suppress local inflammation and prevent cell death despite the absence of a specific uptake mechanism [ 70 ]. These findings underscore the role of inflammation-induced vascular permeability in passive nanoparticle accumulation. In conclusion, passive targeting in AP treatment leverages the inherent pathophysiological features of inflammation, namely, vascular leakiness and impaired lymphatic drainage, to achieve drug delivery. Its key advantages are simplicity, broad applicability, and avoidance of complex surface modifications. Passively accumulated nanomaterials exert anti-inflammatory, antioxidant, and cytoprotective actions by achieving high local concentrations in affected tissues while minimizing systemic exposure. However, a limitation of passive targeting is the potential for nonspecific accumulation at other inflamed sites, which may reduce the targeting precision. Future optimization may include combining passive targeting with active strategies to improve the specificity and efficacy. In contrast to passive targeting, active targeting involves the deliberate guidance of nanoparticles to specific cells or molecular components implicated in disease pathophysiology. In the context of AP, such targets include infiltrating immune cells (e.g., macrophages, neutrophils, and T lymphocytes), damaged PACs, and soluble inflammatory mediators such as cytokines and enzymes. Active targeting is achieved by functionalizing nanoparticles with specific ligands (e.g., antibodies, peptides, carbohydrates, or aptamers) or by employing biomimetic camouflage, whereby the nanoparticle surface is coated with membranes from cells that naturally migrate to sites of inflammation. These strategies promote the selective accumulation of nanotherapeutics in diseased tissues, while minimizing off-target effects and their deposition in healthy organs. One of the most commonly used active targeting strategies for AP is immune cell membrane camouflage. NPs coated with membranes derived from neutrophils or macrophages can evade immune recognition by mimicking the surface of native immune cells, which naturally home to the inflamed tissues. For example, Zhou et al. developed neutrophil membrane-coated nanoparticles loaded with celastrol to treat AP [ 25 ]. These particles successfully crossed the gastrointestinal barrier and selectively accumulated in the inflamed pancreas via the physiological migration pathway of neutrophils. Similarly, Chen et al. [ 41 ] fabricated macrophage-biomimetic nanoparticles loaded with the protease inhibitor, ulinastatin. The macrophage membrane not only extended nanoparticle circulation time but also facilitated their adhesion to inflamed endothelium and penetration into pancreatic tissue via natural membrane-bound adhesion molecules. This strategy enabled the nanoparticles to exert strong therapeutic effects, such as suppressing inflammatory responses, protecting cells from enzymatic self-digestion, and enhancing cell survival [ 41 ]. A comparable approach was demonstrated in a macrophage-mimicking nanotherapy, in which synthetic nanoparticles camouflaged with macrophage membranes selectively accumulated at sites of inflammation [ 46 ]. Another class of active targeting involves ligand-mediated recognition of specific receptors on the target cells. Proinflammatory M1-type macrophages, which infiltrate the pancreas and sustain inflammation, express high levels of Dectin-1 receptor. Karole et al. [ 67 ] designed β-glucan-conjugated polymeric nanoparticles that specifically bind to Dectin-1. In AP models, these nanoparticles accumulate in M1-rich pancreatic tissue, suppress inflammatory signaling, and modulate macrophage polarization, resulting in a strong anti-inflammatory effect. Similarly, mannose-modified nanocapsules loaded with emodin exploit mannose receptor expression on macrophages to enhance their selective uptake. Song et al. demonstrated that mannose decoration significantly improved pancreatic macrophage targeting and reduced the production of inflammatory mediators [ 32 ]. As a result, emodin-loaded nanoparticles downregulate macrophage activation and contribute to the resolution of inflammation. In addition to immune cells, PACs, which are the main exocrine cells of the pancreas, are primary initiators of AP because of their propensity for premature intracellular enzyme activation and calcium overload. Thus, these cells are promising targets for active drug delivery. One relevant molecular target is the L-type amino acid transporter 1 (LAT1), whose expression is upregulated in AP. Li et al. engineered cysteine-functionalized nanoparticles to exploit this transporter and deliver methylprednisolone directly to PACs [ 31 ]. This targeted approach enhanced pancreatic accumulation, improved local anti-inflammatory efficacy, and reduced cytokine levels, offering better protection against PAC injury than untargeted controls. Another innovative system, described by Yan et al. [ 28 ], involves a multistage nanoplatform that combines several targeting elements: an M2 macrophage membrane for endothelial uptake in inflamed regions, octreotide (a somatostatin analog) for PAC recognition via SSTR-2 receptors, and environmental responsiveness to inflammatory stimuli (elevated trypsin and ROS levels) for on-site drug release. Although complex, this system exemplifies the potential of integrated active targeting directed at multiple components of AP pathology, from immune cells and PACs to their mitochondria. A less conventional but highly promising form of active targeting involves binding to soluble inflammatory mediators. In severe AP, proinflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) play central roles in driving systemic inflammation and organ dysfunction. Targeting these mediators directly within the pancreas may offer therapeutic benefits. Chen et al. [ 42 ] developed IL-6-aptamer-functionalized nanoparticles, which act as molecular “traps” to neutralize IL-6 locally in the inflamed pancreas. These particles were simultaneously functionalized with pancreatic lipase to degrade the lipid accumulation characteristic of hyperlipidemic AP. This dual-targeting approach not only blocks inflammatory signaling but also addresses metabolic dysregulation, demonstrating a flexible, noncellular method of active targeting. This dual-targeting approach not only blocks inflammatory signaling but also addresses metabolic dysregulation, demonstrating a flexible, noncellular method of active targeting. In summary, active targeting strategies for AP span a wide range of approaches, from cell membrane-coated biomimetic carriers to ligand-functionalized nanoparticles that target immune cells, PACs, or soluble mediators. These strategies improve the specificity of therapeutic delivery, reduce off-target effects, and increase treatment efficacy by concentrating drug payload at the site of inflammation. Consequently, active targeting enables lower drug dosages, minimizes systemic toxicity, and enhances control over inflammation, oxidative stress, and enzymatic activity in acute pancreatitis.

In recent years, the interest in polymer-based nanocarriers for the treatment of AP has increased. Polymeric nanoparticles enhance drug stability, enable targeted delivery, facilitate controlled release, and improve penetration through physiological barriers. These features are particularly important in AP, where systemic inflammation, oxidative stress, and tissue injury are prominent. PLGA nanoparticles (NPs) are among the most widely used polymeric carriers. For example, Zhou et al. developed PLGA nanoparticles coated with neutrophil membranes and loaded with celastrol [ 25 ]. These particles exhibit a high affinity for inflamed tissue, suppress neutrophil infiltration into the pancreas, and mitigate acute lung injury associated with severe AP [ 25 ]. Another example is PEG–PLGA nanoparticles cloaked with neutrophil membranes (NNPs/CLT), which selectively accumulate in the pancreas of rats with AP, overcome the pancreatic barrier, and achieve targeted distribution [ 25 ]. Similarly, macrophage biomimetic nanoparticles loaded with ulinastatin (MU) exhibited enhanced tropism for inflammatory sites via adhesion proteins present on the macrophage membrane [ 41 ]. These particles also showed favorable biocompatibility and stability in both in vitro and in vivo models [ 41 ]. Surface modifications further enhance the targeting capabilities of the polymeric nanocarriers. For example, cysteine-modified PEGylated nanoparticles selectively accumulate in inflamed pancreatic acinar cells (PACs) [ 31 ]. The nanocarrier pHA@IBNCs was found to concentrate in inflamed regions by targeting intestinal epithelial cells and macrophages, thereby contributing to intestinal barrier repair in severe AP [ 27 ]. More complex delivery systems, such as the “three-stage booster” and Oc-M2M@HMnO 2 -CsA nanoparticles, have been engineered to bypass the pancreatic barrier and target damaged acinar cells [ 28 ]. The M2 macrophage membrane coating promotes adhesion to the inflamed endothelium and guides the particles toward the pancreatic tissue [ 28 ]. Silk fibroin nanoparticles (SF-NPs) coated with neutrophil membranes were used to encapsulate poorly soluble ferulic acid, ensuring controlled release and enhanced bioavailability [ 24 ]. Some polymeric nanocarriers possess intrinsic therapeutic properties. For example, MoSe 2 -PVP nanoparticles mimic natural antioxidant enzymes such as catalase and superoxide dismutase, effectively neutralizing reactive oxygen species (ROS) [ 37 ]. Iridium nanoparticles coated with PVP (IrNP-PVP) display multienzyme-mimetic activity with potent antioxidant and anti-inflammatory effects [ 44 ]. Hollow manganese dioxide nanoparticles (HMnO 2 ) effectively scavenge reactive oxygen species (ROS), protect mitochondria, and exhibit good hemocompatibility even at high concentrations [ 28 ]. A polyphenol-based biomimetic nanodelivery system attenuates severe AP by inhibiting macrophage PANoptosis and excessive pancreatic enzyme secretion [ 34 ]. Other designs, such as macrophage-membrane nanoparticles loaded with melittin and MJ-33, employ a “lure and kill” strategy to neutralize PLA 2 activity and reduce inflammation [ 39 ]. In another study, CQ/TAM-loaded nanoparticles combined with mesenchymal stem cells enhanced immunomodulatory effects and halted disease progression via the iNOS–IDO signaling axis [ 45 ]. In summary, polymeric nanocarriers significantly improve drug delivery in APs by enabling target specificity, overcoming biological barriers, ensuring sustained release, and, in some cases, exerting direct therapeutic effects as nanozymes or immunomodulators. Lipid-based nanocarriers have emerged as powerful platforms for targeted drug delivery in AP. These structures, composed of lipid bilayers or solid lipid matrices, encapsulate a variety of therapeutic agents and protect them from enzymatic degradation, oxidation, and premature metabolism. They offer prolonged systemic circulation, controlled drug release, and improved bioavailability. Several lipid-based nanosystems have been designed to target mitochondrial dysfunction and ROS overproduction, which are key events in the pathogenesis of AP. For example, tafazzin nanoparticles (DSPE-Se-Se-MPEG@TN) were developed to overcome the short half-life and poor bioavailability of the parent drug, enabling targeted delivery to affected cells and modulating mitophagy and P2X7 receptor-mediated mitochondrial ROS production [ 30 ]. Similarly, mitochondria-targeted nanoparticles loaded with kaempferol (DTM@KA NPs), which are based on DSPE-PEG2000 liposomes, enhanced mitochondrial delivery, activated the Nrf2 pathway, and significantly reduced the severity of inflammation [ 38 ]. Hybrid lipid–polymer nanoparticles encapsulating fisetin (FST-loaded LPHNPs) demonstrated enhanced solubility, stability, and systemic availability, thereby increasing their antioxidant and anti-inflammatory activities [ 40 ]. Cysteine-modified PEGylated nanoparticles enable the targeted delivery of methylprednisolone to PACs, suppressing local inflammation while minimizing systemic adverse effects [ 31 ]. By targeting immune cells, mannosylated chitosan–lipid nanocapsules containing emodin (M-CS-E-LNC) facilitate specific delivery to macrophages via mannose receptors. This strategy regulates macrophage polarization and lipid metabolism, ultimately attenuating AP progression [ 32 ]. A novel transformer-like nanocarrier system (TLNS) was designed for oral delivery of curcumin. Upon release in the gastrointestinal tract, TLNS transforms into nanoemulsions that are absorbed through Peyer’s patches and lymphatics, resulting in a 12-fold increase in pancreatic accumulation compared with free curcumin [ 71 ]. The disruption of calcium homeostasis is a central feature of AP. Liposomal nanoparticles carrying the calcium chelator BAPTA-AM (BLN) effectively reduce cytosolic Ca 2+ overload, thereby mitigating early pancreatic injury [ 43 ]. Thus, gas-mediated delivery systems have shown promise. Carbon monoxide-bound hemoglobin vesicles (CO-HbVs) exhibit strong anti-inflammatory and antioxidant properties, significantly reducing organ damage in severe AP [ 53 ]. CO-HbV further modulates macrophage and neutrophil functions, contributing to precise immune regulation [ 62 ]. Macrophage-mimicking nanoparticles coated with plasma membranes demonstrate enhanced retention in inflamed pancreatic tissues, thereby prolonging therapeutic activity while evading clearance by the mononuclear phagocyte system [ 46 ]. These biomimetic systems also inhibited AKT/mTOR signaling, restored autophagic flux, and improved pancreatic structural integrity [ 46 ] (Fig. 4 ). In the same study, compared with their non-coated counterparts, macrophage-biomimetic selenium–polysaccharide nanoparticles (mSe-PPs) provided superior protection against pancreatic injury [ 46 ]. Fig. 4 Macrophage membrane-biomimetic selenylated Poria cocos polysaccharide nanoparticles attenuate acute pancreatitis injury (Reproduced from Shi et al. [ 46 ]. © Elsevier B.V. Distributed under the Creative Commons CC-BY-NC license) Macrophage membrane-biomimetic selenylated Poria cocos polysaccharide nanoparticles attenuate acute pancreatitis injury (Reproduced from Shi et al. [ 46 ]. © Elsevier B.V. Distributed under the Creative Commons CC-BY-NC license) Lipid nanoparticles loaded with mRNA encoding fibroblast growth factor 21 (FGF21) and apolipoprotein A1 (APOA1) provide therapeutic benefits in AP models by increasing systemic protein expression and improving pancreatic histopathology [ 58 ]. Co-delivery of chloroquine (CQ) and tamoxifen (TAM) further enhanced the efficacy of mesenchymal stem cell–based interventions by reducing oxidative stress [ 45 ]. Targeted immune modulation was also achieved through the use of SPIO–clodronate liposomes, which selectively deplete proinflammatory macrophages, thereby alleviating kidney injury and systemic complications in severe AP [ 63 ]. Lipid nanomicelles, such as SinaCurcumin ® , improve curcumin bioavailability and inhibit the TLR4/NF-κB signaling pathway with demonstrated efficacy in both experimental and clinical settings [ 65 , 75 ]. Nanoliposomes containing caffeic acid phenethyl ester (CAPE-loaded NL) regulate Nrf2 and NF-κB pathways, leading to reduced pancreatic injury [ 66 ]. In conclusion, lipid-based nanocarriers represent a versatile and effective strategy for targeted drug delivery in AP. These systems modulate key pathological processes, such as inflammation, oxidative stress, mitochondrial dysfunction, and immune dysregulation, thereby offering considerable therapeutic potential. Owing to their unique physicochemical properties, high functional versatility, and excellent biocompatibility, carbon-based nanomaterials represent a promising class of therapeutic agents for the treatment of AP. Among these materials, carbon dots (CDs) have garnered particular interest because of their facile synthesis, strong intrinsic fluorescence, and pronounced enzyme-mimetic activity, making them suitable for both therapeutic and real-time imaging applications. A key advantage of CDs is their ability to be doped with metal ions, such as cerium or gadolinium, which significantly enhances their catalytic and antioxidant properties. For example, cerium-doped CDs (Ce-CDs) have demonstrated catalase- and superoxide dismutase-like activities, effectively scavenging ROS, which are critical mediators of AP pathogenesis and progression [ 73 ]. In addition, their nanometric size, high hydrophilicity, and favorable safety profile allow for their systemic administration. However, CDs often exhibit rapid renal clearance and a short circulation time. Composite nanosystems have been engineered to overcome these limitations by incorporating biocompatible polymers, such as chitosan, which serve as pH-responsive carriers. This modification enhances systemic retention, minimizes toxicity, and promotes preferential accumulation in inflamed pancreatic tissues via the enhanced permeability and retention (EPR) effect, also referred to as the ELVIS phenomenon (extravasation through leaky vasculature and inflammatory cell-mediated sequestration) [ 73 ]. The incorporation of CDs into multifunctional platforms, such as CRCS (CDs/RES@CS nanoparticles), enables a multimodal approach to AP treatment by combining ROS neutralization, immunomodulation, and live imaging. The addition of bioactive molecules such as resveratrol (RES) further augments therapeutic efficacy. RES not only suppresses ROS generation but also promotes macrophage repolarization from the proinflammatory M1 phenotype to the anti-inflammatory M2 phenotype, a process critical for mitigating tissue damage in AP [ 73 ]. In conclusion, carbon-based nanostructures offer a multifunctional therapeutic platform for the management of AP, facilitating targeted delivery, attenuating oxidative stress, and modulating immune response. Organometallic nanoparticles (OMNs) represent a promising class of nanotherapeutics for the treatment of AP, owing to their unique ability to integrate targeted delivery, catalytic activity, and direct modulation of pathophysiological pathways. One of the most notable features of OMNs is their antioxidant activity. For example, copper-based metal–organic frameworks (Cu-MOFs) function as nanozymes, mimicking the activity of endogenous antioxidant enzymes such as superoxide dismutase (SOD) and catalase, thereby eliminating hydroxyl radicals and mitigating oxidative stress in pancreatic tissues [ 72 ]. A similar effect has been demonstrated by Prussian blue-based nanozymes (PBzymes), which contribute to ROS detoxification and attenuation of oxidative damage (Fig. 5 ) [ 61 ]. Additionally, mitochondria-targeted tungsten-based nanodots (mTWNDs) selectively scavenge mitochondrial ROS (mtROS) in PACs, which is one of the earliest and most critical events in AP pathogenesis [ 52 ]. Fig. 5 Schematic illustration of the prophylactic effect of PBzyme in acute pancreatitis. PBzyme scavenges ROS and suppresses TLR/NF-κB-mediated inflammatory signaling, thereby modulating oxidative stress- and inflammation-related genes and attenuating mitochondrial dysfunction, cell death, and pancreatic tissue injury (Reproduced from Xie et al. [ 61 ]. © Ivyspring International Publisher. Distributed under the terms of the Creative Commons Attribution License, CC BY 4.0) Schematic illustration of the prophylactic effect of PBzyme in acute pancreatitis. PBzyme scavenges ROS and suppresses TLR/NF-κB-mediated inflammatory signaling, thereby modulating oxidative stress- and inflammation-related genes and attenuating mitochondrial dysfunction, cell death, and pancreatic tissue injury (Reproduced from Xie et al. [ 61 ]. © Ivyspring International Publisher. Distributed under the terms of the Creative Commons Attribution License, CC BY 4.0) In addition to their antioxidant effects, OMNs exhibit anti-inflammatory activity by modulating canonical inflammatory signaling pathways. For example, PBzymes inhibit the TLR/NF-κB axis, resulting in reduced expression of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 [ 61 ]. Composite nanoparticles, such as EMO@ZIF-8/heparin, which incorporate zeolitic imidazolate framework-8 (ZIF-8) as a porous carrier, modulate the JNK signaling cascade in macrophages and suppress the release of inflammatory mediators [ 74 ]. mTWNDs also attenuate STING-mediated activation of the innate immune response, which plays a pivotal role in sterile inflammation during AP [ 52 ]. A key advantage of several OMNs is their ability to target mitochondria and restore mitochondrial function. Given that mitochondrial dysfunction is an early and central event in AP pathogenesis [ 72 ], targeting these organelles would enable multifaceted therapeutic interventions. NPs such as Cu-MOFs, mTWNDs, and EMO@ZIF-8/heparin can penetrate the mitochondria of acinar cells, restore the mitochondrial membrane potential (ΔΨm), prevent the opening of the mitochondrial permeability transition pore (mPTP), and reduce mtROS production [ 52 , 72 , 74 ]. Moreover, Cu-MOFs have been shown to activate mitophagy, promote the clearance of damaged mitochondria, and preserve cellular homeostasis [ 72 ]. With respect to cytoprotection, OMNs exhibit significant antiapoptotic effects. Both Cu-MOFs and mTWNDs downregulate the expression of pro-apoptotic markers, such as Bax and caspase-3, while upregulating the anti-apoptotic protein Bcl-2, thereby protecting acinar cells from programmed cell death [ 52 , 72 ]. The use of biomimetic carriers, such as MV-UiO-ED (based on UiO-66-NH 2 with a macrophage membrane coating), facilitates selective delivery to injured pancreatic tissues and significantly reduces edema, necrosis, and cellular damage [ 22 ]. Similarly, ZIF-8-based delivery systems, including EMO@ZIF-8/heparin, mitigate apoptosis and improve both the morphological and functional integrity of the pancreas [ 74 ]. Taken together, these findings indicate that organometallic nanoparticles exert potent therapeutic effects on AP by providing antioxidant protection, modulating inflammatory signaling, preserving mitochondrial function, and enhancing cytoprotection. Metal-based, metal oxide, and metalloid nanoparticles constitute a robust class of nanotherapeutic agents with the capacity to modulate multiple pathogenic pathways in AP. These nanosystems integrate antioxidant, anti-inflammatory, cytoprotective, and immunomodulatory functions, making them particularly well-suited for multimodal therapeutic interventions in AP. Yttrium oxide nanoparticles (Y 2 O 3 NPs) exhibit strong radical-scavenging capacity, restoring ΔΨm in macrophages, reducing ROS and superoxide levels, suppressing amylase and lipase activity, and alleviating mitochondrial stress [ 33 ]. Similarly, cerium oxide nanoparticles (CeO 2 NPs) mimic the enzymatic activities of SOD and catalase, thereby mitigating lipopolysaccharide (LPS)-induced oxidative stress and inflammatory responses in macrophages [ 48 ]. Ultrasmall iridium nanoparticles (IrNPs) coated with polyvinylpyrrolidone (PVP) also demonstrate potent antioxidant and anti-inflammatory properties, contributing to the attenuation of pathological features in experimental models of AP [ 44 ]. Among metalloid-based nanotherapeutics, selenium nanoparticles (SeNPs) have shown considerable promise. Porous silica-coated SeNPs significantly reduced inflammation and oxidative injury in cerulein-induced AP models [ 36 ]. Green-synthesized SeNPs derived from Coleus forskohlii extract enhanced exocrine pancreatic function and provided broad cytoprotective effects [ 35 ]. In vivo studies have demonstrated that nanoselenium can restore both endocrine and exocrine pancreatic function in the context of AP [ 23 ]. Additionally, selenium-modified polysaccharide nanoparticles derived from Eucommia ulmoides exert anti-inflammatory, antioxidant, and intestinal barrier–protective effects in models of severe AP [ 46 ]. Metallic and metalloid nanoparticles not only scavenge ROS directly but also exhibit intrinsic nanozyme-like activities, mimicking a range of enzymatic functions. For example, MoSe 2 –PVP nanoparticles possess multi-enzyme mimetic activities, including catalase, SOD, peroxidase, and glutathione peroxidase, thereby enabling comprehensive neutralization of oxidative stress and promotion of cytoprotection [ 37 ]. A biomimetic nanoenzyme system based on Prussian blue (PB), encapsulated in a ZIF-8 framework and loaded with celastrol has been shown to activate autophagy and selectively accumulate in inflamed pancreatic tissues, providing dual mechanisms for ROS clearance and suppression of inflammation [ 47 ]. PB-based nanozymes also inhibit the TLR/NF-κB pathway, thereby contributing to pancreatic tissue homeostasis and restoring the intestinal epithelial barrier [ 27 ]. Innovative nanotherapeutic approaches include the use of hollow manganese dioxide nanoparticles (HMnO 2 NPs), which act at several key stages of AP pathogenesis. These particles normalize intracellular calcium homeostasis, restore mitochondrial function, inhibit autodigestive enzyme activation, and effectively scavenge ROS [ 28 ]. Notably, HMnO 2 NPs also suppressed the activation of the NLRP3 inflammasome, a central component of sterile inflammation, and the innate immune response in AP [ 28 ]. Several nanoparticle systems have been engineered to address specific AP phenotypes. For example, mesoporous silica (SiO 2 ) nanoparticles functionalized with IL-6 aptamers and lipase target hyperlipidemic APs by binding circulating IL-6 and hydrolyzing triglycerides, thereby modulating underlying metabolic and inflammatory abnormalities [ 42 ]. Another example is the inflammation-responsive FePTX@CM nanoparticle system, which reduces macrophage PANoptosis, suppresses exocrine enzyme release, and modulates the ZBP1 and NF-κB signaling pathways, offering multitarget ed protection in severe AP (Fig. 6 ) [ 34 ]. Fig. 6 Schematic illustration of FePTX@CM nanoparticle preparation and therapeutic mechanisms in severe acute pancreatitis. After intravenous injection, FePTX@CM NPs target the injured pancreas, where released PTX inhibits Zbp1-mediated macrophage PANoptosis and PYD suppresses mtROS/Golgi stress-mediated enzyme and proinflammatory mediator release, thereby reducing immune cell recruitment, inflammation, and acinar cell damage (Reproduced from Wu et al. [ 34 ]. © Elsevier B.V. Distributed under the Creative Commons CC-BY-NC-ND license) Schematic illustration of FePTX@CM nanoparticle preparation and therapeutic mechanisms in severe acute pancreatitis. After intravenous injection, FePTX@CM NPs target the injured pancreas, where released PTX inhibits Zbp1-mediated macrophage PANoptosis and PYD suppresses mtROS/Golgi stress-mediated enzyme and proinflammatory mediator release, thereby reducing immune cell recruitment, inflammation, and acinar cell damage (Reproduced from Wu et al. [ 34 ]. © Elsevier B.V. Distributed under the Creative Commons CC-BY-NC-ND license) In conclusion, metal-based oxide and metalloid nanoparticles exhibit significant therapeutic potential in acute pancreatitis by targeting oxidative stress, mitochondrial dysfunction, inflammation, and epithelial barrier integrity. Their versatility supports the development of personalized, targeted, and disease-specific nanotherapeutic strategies for effective AP management. Biological and biogenic nanostructures play pivotal roles in enhancing the pharmacological performance of therapeutics in AP, effectively addressing key challenges such as rapid systemic clearance, low solubility, and limited tissue specificity. One of the most effective strategies involves the use of biomimetic nanoparticles coated with cell-derived membranes, which markedly improves the ability of nanosystems to bypass physiological barriers and selectively accumulate in inflamed pancreatic tissues [ 22 ]. For example, UiO-66-NH 2 nanoparticles coated with macrophage membranes demonstrated efficient emodin delivery to inflamed sites, leveraging the innate homing capabilities of the source cells [ 22 ]. These systems successfully penetrate the pancreatic barrier, exhibit high tissue localization, and markedly enhance intracellular uptake, reaching up to 80% for certain therapeutic compounds [ 22 , 25 ]. Moreover, macrophage-mimicking nanoparticles prolong circulation time and enhance targeting efficacy by evading clearance by the mononuclear phagocyte system [ 46 ]. Biogenic nanocarriers can also improve pharmacokinetics by increasing drug solubility and bioavailability. For example, bilirubin-loaded silk fibroin nanoparticles (BRSNPs) address the solubility and toxicity limitations of free bilirubin [ 26 ]. These nanoparticles penetrate inflamed pancreatic tissue and release bilirubin in an enzyme-responsive manner, offering pronounced therapeutic benefits by suppressing oxidative stress, reducing cytokine production, and inhibiting immune cell infiltration [ 26 ]. Likewise, ferulic acid-loaded silk fibroin nanoparticles coated with neutrophil membranes exhibit enhanced tissue targeting and improved systemic bioavailability [ 24 ]. Targeted drug delivery is another key advantage of biological nanostructures. Neutrophil-coated nanoparticles loaded with celastrol selectively accumulate in the pancreas, efficiently cross the pancreatic barrier, and significantly reduce serum amylase and myeloperoxidase (MPO) levels and systemic toxicity [ 25 ]. Some biogenic nanostructures also exhibit intrinsic therapeutic activities. Green-synthesized selenium nanoparticles derived from Coleus forskohlii extract improved pancreatic function in a rat model of AP [ 35 ]. In a study by Farghly et al., nanoformulated Moringa oleifera extract, administered with or without low-dose γ-irradiation (0.25 Gy), significantly decreased the levels of lipase, amylase, C-reactive protein, and glucose while restoring insulin and IGF-1 levels in an L-arginine-induced AP model [ 76 ]. Histological analysis revealed reduced necrosis, hemorrhage, and lymphocytic infiltration. The combination with γ-irradiation exerted a synergistic effect, underscoring the potential of nanophytotherapy in AP [ 76 ]. Advanced systems, such as MPBZC, an acid-responsive biomimetic nanoenzyme composed of hollow Prussian blue (PB) cores encapsulated in ZIF-8, exert potent anti-inflammatory and mitochondria-protective effects by simultaneously scavenging ROS and promoting the clearance of damaged mitochondria (Fig. 7 ) [ 47 ]. Fig. 7 Schematic of MPBZC nanozyme preparation and therapeutic mechanism in severe acute pancreatitis. A Construction of acid-responsive, macrophage-membrane-camouflaged PB@ZIF-8 nanozymes loaded with celastrol (MPBZC); in acidic conditions ZIF-8 degrades, releasing celastrol and exposing the PB core for ROS scavenging. B Targeting of inflamed pancreatic tissue via P-selectin–mediated adhesion, nanoparticle internalization, and enhancement of mitophagy and autophagic flux, which restores mitochondrial membrane potential and reduces ROS, pancreatic injury, and inflammatory cytokines (Reproduced from Wang et al. [ 47 ]. © American Chemical Society. Distributed under the Creative Commons CC-BY-NC-ND license) Schematic of MPBZC nanozyme preparation and therapeutic mechanism in severe acute pancreatitis. A Construction of acid-responsive, macrophage-membrane-camouflaged PB@ZIF-8 nanozymes loaded with celastrol (MPBZC); in acidic conditions ZIF-8 degrades, releasing celastrol and exposing the PB core for ROS scavenging. B Targeting of inflamed pancreatic tissue via P-selectin–mediated adhesion, nanoparticle internalization, and enhancement of mitophagy and autophagic flux, which restores mitochondrial membrane potential and reduces ROS, pancreatic injury, and inflammatory cytokines (Reproduced from Wang et al. [ 47 ]. © American Chemical Society. Distributed under the Creative Commons CC-BY-NC-ND license) Nanocarriers offer solutions for overcoming complex physiological barriers such as the pancreatic–blood barrier (PBB). Empagliflozin (EMP), a drug with poor water solubility and low oral bioavailability, was reformulated into a self-nanomicellizing system using rebaudioside A (RA-EMP). This approach markedly enhances its solubility, systemic availability, and therapeutic efficacy in AP, as evidenced by reductions in oxidative stress and proinflammatory cytokine levels [ 56 ]. Certain nanoparticles have been engineered to selectively target key immune cells, such as macrophages, which play a central role in AP pathogenesis. During AP, macrophages infiltrate the pancreas and shift toward a proinflammatory M1 phenotype, releasing cytokines and ROS that exacerbate injury [ 67 , 73 ]. Thus, reprogramming macrophage polarization and eliminating ROS are promising therapeutic strategies [ 73 ]. β-Glucan–conjugated polymeric nanoparticles (GNPs) target inflammatory macrophages via the Dectin-1 receptor. When loaded with amlexanox (AMX-GNPs), they enable trypsin-responsive drug release and exhibit strong anti-inflammatory effects by modulating macrophage polarization and cytokine secretion [ 67 ]. Importantly, these nanoparticles reach the pancreatic tissue through the gut–lymphatic route after oral administration [ 67 ]. Another innovative example is tetrahedral framework nucleic acids (tFNAs), which effectively suppress inflammation and prevent pathological cell death in both pancreatic and extrapancreatic tissues in murine AP models [ 70 ]. These nanostructures modulate inflammatory biomarkers and reduce cytokine production at both local and systemic levels. Exosomes are also emerging as promising biogenic nanocarriers in AP. Exosomes isolated from the plasma and bronchoalveolar lavage fluid of emodin-treated rats with severe AP showed therapeutic activity via altered miRNA expression profiles, particularly through the modulation of miR-29a-3p, which contributed to the attenuation of acute lung injury [ 57 ]. Heparin-modified emodin nanocarriers (EMO@ZIF-8/heparin, HEZ) have been developed for the specific delivery of emodin to inflamed pancreatic tissues by targeting CD44-positive macrophages [ 74 ]. HEZ exhibited enhanced uptake by macrophages within the inflammatory microenvironment, restored ΔΨm, reduced oxidative stress, and suppressed proinflammatory cytokine levels [ 74 ]. Furthermore, selective accumulation and retention of the nanocarrier in pancreatic tissue were observed, blocking the systemic inflammatory cascade and significantly mitigating pathological damage in both pancreatic and pulmonary tissues, thereby improving survival in mice with severe AP [ 74 ]. Particular attention has been paid to an innovative strategy involving the fusion of immunoengineered mitochondria with neutrophil membranes (nMITO). These nanostructures provide targeted delivery to injured sites, exhibit potent anti-inflammatory effects, and support cellular recovery [ 49 ]. Through interactions with β-integrins, nMITO selectively targets damaged endothelial cells and is transported to affected areas via tunneling nanotubes, thereby enhancing the regulation of inflammation and maintaining tissue homeostasis [ 49 ]. Biomimetic nanostructures are also capable of efficiently overcoming physiological barriers, particularly the pancreatic–blood barrier (PBB), which restricts the penetration of conventional drugs into the pancreatic parenchyma [ 52 ]. For example, tannic acid- and melanin-modified tungsten-based nanoparticles (mTWNDs) penetrate the compromised PBB owing to the affinity of tannic acid for type III collagen and the TOM20 protein on the outer mitochondrial membrane, enabling the selective elimination of mtROS in acinar cells (Fig. 8 ) [ 52 ]. The small particle size of mTWNDs (10.9 nm) further facilitates their accumulation at sites of injury by allowing passage through endothelial gaps formed as a result of vascular wall disruption [ 52 ]. Fig. 8 Schematic illustration of mTWND design, characteristics, and mechanisms in acute pancreatitis. A mTWNDs are synthesized by TA/dopamine-mediated reduction of phosphotungstic acid. B By binding type III collagen and mitochondrial TOM20, they recognize damaged blood–pancreas barrier (BPB) and injured pancreatic acinar cell mitochondria. C Their ultrasmall size enables penetration through the impaired BPB and pancreatic accumulation. D mTWNDs scavenge ROS, inhibit mitochondrial apoptosis, and block cGAS/STING-mediated inflammatory signaling in macrophages, thereby attenuating acute pancreatitis (Reproduced from Wang et al. [ 52 ]. © John Wiley & Sons, Inc. Distributed under the terms of the Creative Commons Attribution License, CC BY 4.0) Schematic illustration of mTWND design, characteristics, and mechanisms in acute pancreatitis. A mTWNDs are synthesized by TA/dopamine-mediated reduction of phosphotungstic acid. B By binding type III collagen and mitochondrial TOM20, they recognize damaged blood–pancreas barrier (BPB) and injured pancreatic acinar cell mitochondria. C Their ultrasmall size enables penetration through the impaired BPB and pancreatic accumulation. D mTWNDs scavenge ROS, inhibit mitochondrial apoptosis, and block cGAS/STING-mediated inflammatory signaling in macrophages, thereby attenuating acute pancreatitis (Reproduced from Wang et al. [ 52 ]. © John Wiley & Sons, Inc. Distributed under the terms of the Creative Commons Attribution License, CC BY 4.0) Nanostructures also exhibit the capacity to precisely modulate inflammatory responses. For example, PC@PLGA polymeric nanoparticles coated with a hybrid shell derived from platelet extracellular vesicles and membranes expressing calreticulin can induce programmed removal of activated neutrophils (PrCRs) via macrophage-mediated mechanisms [ 54 ]. In this context, calreticulin acts as a “senescence signal” that triggers anti-inflammatory processes and prevents secondary tissue damage [ 54 ]. Finally, the biogenic nanostructures support the regeneration of cellular functions. Mitochondrial transplantation via nMITO facilitates the restoration of cellular bioenergetics through fusion with endogenous mitochondria [ 49 ]. This approach may induce mitophagy, promote the degradation of damaged organelles, increase ATP synthesis, and restore cellular functional integrity [ 49 ]. In summary, biological and biogenic nanostructures represent highly promising therapeutic platforms for overcoming the limitations of conventional pharmacotherapy in AP. They can improve drug solubility and bioavailability, enable targeted delivery, modulate inflammatory responses, and reduce oxidative stress.

This systematic review was conducted in accordance with the PRISMA 2020 guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [ 21 ] (Fig. 1 ). A structured literature search was performed using the international databases PubMed, Scopus, and Google Scholar to identify studies that investigated nanotechnology-based therapeutic strategies for acute pancreatitis. The following keywords were used: “acute pancreatitis,” “nanomedicine,” “nanomaterials,” “nanoparticles,” and “nanodrugs.” The review protocol registered in PROSPERO (CRD420251239676). Fig. 1 PRISMA diagram for the study PRISMA diagram for the study In total, 316 records were identified. During the primary screening, 96 duplicates and 132 irrelevant publications were excluded. Consequently, 88 articles were selected for full-text assessment. One article was requested but was unavailable, leaving 87 studies for eligibility assessment. Following the full-text review, 12 articles were excluded because of the absence of therapeutic focus on nanodrugs. Thus, 75 articles were considered eligible for inclusion. Among them, 12 were review articles, 4 were diagnostic studies, 1 focused on chronic pancreatitis, and 2 were ex vivo studies, none of which met the inclusion criteria. Ultimately, 56 original studies were included in the final qualitative analysis [ 22 – 77 ]. The eligibility criteria were as follows: (1) experimental or clinical studies evaluating nanotechnology-based therapeutic strategies for AP, and (2) studies conducted in animal models or human subjects. The primary outcomes included the mechanisms of action and therapeutic efficacy of the nanodrugs in AP. The quality of the animal experiments described in the papers included in the full analysis was assessed using the SYRCLE risk of bias (RoB) assessment tool (Figs.  2 and 3 ). The RoB tool for animal studies contains 10 items related to selection bias, performance bias, detection bias, attrition bias, reporting bias, and other sources of bias. Two reviewers performed the RoB assessment, and any disagreements were resolved by consensus. If consensus could not be reached, a third reviewer was consulted. Inter-rater agreement between the two reviewers was assessed using Cohen’s kappa coefficient (κ). For each of the 56 included studies, both reviewers independently rated risk of bias in SYRCLE domains D1–D6 using three categorical levels: “Low,” “High,” or “Unclear.” Where necessary, equivalent labels (e.g. “No information”) were harmonised to the “Unclear” category prior to analysis. Cohen’s kappa was calculated for all domains combined (overall κ) and separately for each individual domain, treating the three levels as nominal categories and using the standard formula κ = (Po − Pe) / (1 − Pe), where Po is the observed proportion of agreement and Pe is the expected agreement by chance. For domains in which all ratings by both reviewers fell into a single category (no variability), κ could not be estimated, and agreement for these domains was reported descriptively as 100%. Using this approach, the overall inter-rater agreement was almost perfect (κ = 0.86) with an observed agreement of 93.2%. Domain-specific κ values were 0.55 for D1 (76.8% agreement), 0.00 for D2 (98.2% agreement, with very high expected chance agreement due to the dominance of the “Unclear” category), 0.67 for D3 (85.7% agreement), 0.93 for D4 (98.2% agreement), and 1.00 for D5 (100% agreement). For D6, all ratings from both reviewers were “Low,” so κ could not be estimated, although the raw agreement in this domain was 100%. Notably, despite a similarly high raw agreement of 98.2% in domains D2 and D4, Cohen’s κ differed markedly (0.00 vs. 0.93). This discrepancy reflects the strong prevalence of the “Unclear” category in D2, which leads to a very high expected chance agreement (Pe) and thus a κ close to zero. In D4, the ratings were more evenly distributed across categories, resulting in a much lower Pe and, consequently, a κ indicative of almost perfect agreement. The extracted data included the type of nanoparticle, composition, nanocarrier material, targeting strategy, mechanism of action, experimental model characteristics (animal species and strain, method of AP induction, dosing regimen, route and timing of administration, and duration of follow-up), and main outcome measures (biochemical markers, histological injury scores, organ dysfunction indices, and survival). Study-level details are summarized in Table  1 , and high-level syntheses of nanocarrier classes, targeting strategies, mechanisms of action, and key outcomes are provided in Table  2 . Table 1 Nanodrugs investigated in acute pancreatitis Drug name and composition Carrier le Targeting Therapeutic effect Mechanism of action MVs-UiO-ED [ 22 ] Emodin (ED) UiO-66-NH 2 Macrophage membranes (MVs) Organometallic nanoparticles Biological and biogenic nanostructures Passive and active Anti-inflammatory Cytoprotective Immunomodulatory Reduction in α-amylase and lipase levels; binding of proinflammatory cytokines Attenuation of acinar cell damage, edema, and necrosis Binding of endotoxins and cytokines Nano-Se [ 23 ] Selenium Metal nanoparticles Passive Antioxidant Anti-inflammatory Immunomodulatory Cytoprotective Protective pro-apoptotic Reduction in MDA and NO levels; increase in total antioxidant capacity Reduction in serum IL-1β and NF-κB expression in tissues Suppression of IL-1β, NF-κB, NO production Preservation of acinar and islet architecture Decrease in Bcl-2 expression, promoting apoptosis over necrosis FA-SF-NPs [ 24 ] Ferulic acid (FA) Silk fibroin nanoparticles (SF-NPs) Neutrophil membrane coating Polymeric nanocarriers Biological and biogenic nanostructures Active Antioxidant Anti-inflammatory Immunomodulatory Cytoprotective Reduction in MDA, increase in SOD, GSH/GSSG, GPx Decrease in IL-1β, IL-6, TNF-α Cytokine and inflammation suppression Protection of acinar cells and reduction of histopathological damage NPs/CLT [ 25 ] Celastrol (CLT) PEG-PLGA Neutrophil membranes Polymeric nanocarriers Biological and biogenic nanostructures Passive and active Anti-inflammatory Immunomodulatory Cytoprotective Reduction in TNF-α, IL-6, IL-1β, NF-κB, MPO; decreased infiltration, edema, amylase Suppression of neutrophil activity and cytokines Acinar cell protection, reduction in necrosis and infiltration BRSNPs [ 26 ] Bilirubin Silk fibroin (SF) Biological and biogenic nanostructures Passive and active Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Reduction of ROS and MDA; increased SOD activity; activation of Nrf2/HO-1 pathway Inhibition of NF-κB activation; reduced expression of TNF-α, ICAM-1, MPO, CD68 Protection of acinar cells from oxidative damage; reduced necrosis; improved cell viability Lowered caspase-3 levels in pancreatic tissue pHA@IBNC [ 27 ] Epigallocatechin gallate (EGCG) Interleukin-22 (IL-22) Hyaluronic acid (HA) Polymeric nanocarriers Metal/metal oxide nanoparticles Passive and active Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Reduction of ROS; restoration of redox balance in pancreatic and intestinal tissues Suppression of TNF-α, IL-1β, IL-6 expression; inhibition of NF-κB activation; decreased infiltration of macrophages (CD86+), neutrophils (Ly6G+) Enterocyte cytoskeleton recovery; reduced cell stress; intestinal and acinar cell protection Reduced TUNEL-positive cells and caspase-3 expression Oc-2 M@HMnO 2 CsA [ 28 ] Manganese dioxide nanoparticles (HMnO 2 ) M2-like macrophage membranes Octreotide (Oc) Cyclosporin A (CsA) Metal/metal oxide nanoparticles Biological and biogenic nanostructures Polymeric nanocarriers Passive and active Antioxidant Anti-inflammatory Mitochondria-targeted Immunomodulatory Cytoprotective Anti-apoptotic Reduction of ROS and generation of O 2 Inhibition of IL-6, IL-1β secretion and other proinflammatory cytokines; suppression of caspase-11 and GSDME-mediated pyroptosis Inhibition of mPTP opening, recovery of ΔΨm, reduced Cyt-C release, decreased mtROS Phagocytosis avoidance (CD47 signal), macrophage repolarization to anti-inflammatory phenotype (CD163⁺) Enhanced acinar cell viability, preservation of ATP and MMPs; reduction of intracellular Ca 2+ Suppression of Apaf-1 → Caspase-11 → Caspase-3 pathway, decreasing apoptosis; reduced TUNEL-positive cells CA-NPs [ 29 ] Cinnamic acid Physically dispersed pure organic nanoparticles Passive Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Reduction of MDA, GSSG/GSH ratio; increase in GSH Suppression of NF-κB and NLRP3 expression; reduced inflammatory cell infiltration Improved pancreatic morphology, restoration of acinar cell structure Decreased caspase-3, ASK1 levels; inhibition of MAPK pathway DSPE-Se-Se-MPEG@TN [ 30 ] DSPE-Se-Se-MPEG liposomes Tuftsin (TN) Perfluorooctyl bromide (PFOB) Lipid nanoparticles Active targeting Antioxidant Anti-inflammatory Mitochondria-targeted Immunomodulatory Cytoprotective Anti-apoptotic Reduction in MDA; increase in GSH; activation of Nrf2/HO-1 pathway Decrease in IL-6, IL-1β, MPO; blockade of P2X7-NLRP3 Mitochondrial colocalization; restoration of ΔΨm; impact on PINK1/Parkin pathway Modulation of P2X7/NLRP3 Preservation of mitochondrial structures; improved cell survival Reduction of Bax and increase in Bcl-2 in pancreatic tissue MP/CP-NPs [ 31 ] Methylprednisolone Cysteine PEG nanoparticles Polymeric nanocarriers Lipid nanoparticles Passive and active Anti-inflammatory Cytoprotective Reduction of TNF-α, IL-6, MPO levels Decrease in acinar cell necrosis M-CS-E-LNC [ 32 ] Emodin Mannosylated chitosan (Man-CS) Lipid nanoparticles Active Anti-inflammatory Immunomodulatory Cytoprotective Inhibition of TNF-α, IL-6, iNOS; macrophage polarization to M2 Induction of M1 to M2 macrophage transition via CPT1-dependent metabolic reprogramming Protection of acinar cells from inflammatory damage Nanoyttrium (NY) [ 33 ] Yttrium oxide (Y 2 O 3 ) Metal/metal oxide nanoparticles Passive Antioxidant Anti-inflammatory Mitochondria-targeted Cytoprotective Reduction in ROS, superoxide anion, MDA; increase in GSH, SOD, catalase; modulation of Nrf2/NQO1 signaling Suppression of IL-1β, IL-6, IL-17, TNF-α expression; inhibition of NF-κB activation (p65 nuclear translocation) Restoration of ΔΨm; reduced mitochondrial superoxide production Protection of acinar cells from oxidative and inflammatory injury; reduced histological signs of necrosis, edema, vacuolization FePTX@CM NPs [ 34 ] Proanthocyanidin (PYD) Pentoxifylline (PTX) Iron ions Macrophage membranes Polymeric nanocarriers Metallic nanoparticles Biological and biogenic nanostructures Passive and active Antioxidant Anti-inflammatory Mitochondria-targeted Immunomodulatory Cytoprotective Anti-apoptotic Reduction of mtROS in acinar cells; blockade of mtROS-mediated Golgi stress Inhibition of IL-1β, IL-6 secretion, NF-κB activity, neutrophil recruitment Reduction of mtROS; improved mitochondrial function in acinar cells Reduction of macrophage PANoptosis by regulating Zbp1, RIPK3, Casp6 expression Decreased secretion of amylase and lipase, protecting acinar cells from autodigestion Blockade of PANoptosis (apoptosis, necroptosis, pyroptosis) especially in macrophages Se-NPs [ 35 ] Selenium Metalloid nanoparticles Biological and biogenic nanostructures Passive Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Increased antioxidant potential; reduced MDA and NO in pancreatic tissue Decreased IL-1β levels Normalization of glycemia, insulin, and HOMA-β Reduction of Bcl-2 expression in pancreatic tissues Se@SiO 2 [ 36 ] Selenium Silicon dioxide Oxide and metalloid nanoparticles Passive Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Reduction of ROS, MDA, MPO; increase in GSH, SOD; activation of Nrf2/HO-1/NQO1 signaling pathway Decreased IL-6, IL-1β, TNF-α levels; inhibition of TLR4/MyD88/p-p65 (NF-κB) signaling cascade Reduced injury in pancreas, lungs, liver, and kidneys Decrease in TUNEL-positive cells MoSe 2 -PVP NPs [ 37 ] Molybdenum diselenide (MoSe2) Polyvinylpyrrolidone (PVP) Metalloid nanoparticles Polymeric carriers Passive Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Enzymatic mimicry of CAT, SOD, POD, GPx; scavenging of H 2 O 2 , ·OH, ·O 2 − , DPPH Reduction of TNF-α, IL-1β, IL-6 levels Protection of cells from H 2 O 2 -induced cytotoxicity Reduction of apoptotic cell percentage DTM@KA NPs [ 38 ] Kaempferol Thioacetal Lipid-polymer conjugate DSPE-PEG2000 Lipid nanoparticles Passive and active Antioxidant Anti-inflammatory Mitochondria-targeted Anti-apoptotic Reduction of ROS; increase in GSH/GSSG; activation of Nrf2/HO-1 pathway Decrease in IL-1β, IL-6, MPO, p-p65, caspase-3 Activation of TOM20–STAT6–Drp1/PINK1–Parkin pathway Increase in Bcl-2, reduction in Bax and caspase-3 MΦ-NP(L&K) [ 39 ] Melittin and MJ-33 Macrophage membranes Polymeric nanoparticles Biological and biogenic nanostructures Passive and active Anti-enzymatic Anti-inflammatory Immunomodulatory Cytoprotective Anti-apoptotic Neutralization of phospholipase A2 activity Reduction of IL-6, TNF-α, IL-1β; inhibition of NF-κB activation Suppression of immune-inflammatory response via macrophage interaction Protection of acinar cells from necrosis Reduction of apoptosis in acinar cells confirmed by flow cytometry FST-loaded LPHNPs [ 40 ] Fisetin (FST) Lipid-polymer hybrid nanoparticles Lipid-polymer hybrid nanoparticles Passive Partially active Antioxidant Anti-inflammatory Cytoprotective Reduction of MDA and preservation of GSH in pancreatic tissues Decrease in expression of NF-κB, TLR4, IL-1β, TNF-α, IL-6, NLRP3, CRP Reduction of necrosis, edema, infiltration MU [ 41 ] Ulinastatin PEG-PLGA Macrophage membrane Polymeric nanoparticles Biological and biogenic nanostructures Passive and active Anti-inflammatory Cytoprotective Immunomodulatory Reduction of IL-6 and TNF-α in serum and pancreatic tissue; inhibition of IκBα/p65/NF-κB pathway Preservation of HPDE6-C7 (normal pancreatic ductal epithelial cells) viability Immunomimicry enabling phagocytosis evasion; modulation of local immune response via cytokine interaction MSN-APT-LP [ 42 ] Silicon IL-6 aptamer Lipase Metalloid nanoparticles Active Anti-inflammatory Immunomodulatory For enzyme delivery and activation Binding of IL-6 to reduce proinflammatory response IL-6 depletion mediates immunomodulation Triglyceride decomposition in plasma; reduction of lipotoxicity and pancreatic burden BAPTAAM-loaded LN [ 43 ] (BLN) BAPTA-AM Liposomal nanoparticles Lipid nanoparticles Passive Antioxidant Anti-inflammatory Immunomodulatory Cytoprotective Anti-apoptotic Reduction of ROS in AR42J cells; decreased MDA; increased SOD and GSH Lower TNF-α and IL-6 in serum and RAW264.7 cells; inhibited macrophage activation; reduced cathepsin B activity Suppression of macrophage activation and cytokine release (IL-6, TNF-α) in response to LPS Protection of acinar cells from apoptosis, necrosis, autoactivation of enzymes; normalization of Ca 2+ levels Inhibition of TNF-α/cathepsin B signaling pathway IrNP-PVP [ 44 ] Iridium Polyvinylpyrrolidone Metal nanoparticles Polymeric nanocarriers Passive Antioxidant Anti-inflammatory Mitochondria-targeted Cytoprotective Anti-apoptotic Catalase-, peroxidase-, and SOD-like activity; scavenging of H 2 O 2 , ·OH, ·O 2 − , DPPH· Reduction of TNF-α, IL-1β, IL-6 in serum and pancreatic tissue Restoration of mitochondrial structure, improvement of ΔΨm, increased activity of mitochondrial respiratory chain complexes I and IV Improved viability of RAW264.7 and HUAEC cells after LPS and H 2 O 2 exposure TUNEL and Annexin-V/PI testing confirm decreased apoptosis in cells and tissues MSC + ICT-NPs [ 45 ] Interferon-gamma Chloroquine Tamoxifen PLGA nanoparticles Polymeric nanocarriers Lipid nanocarriers Passive Anti-inflammatory Immunomodulatory Cytoprotective Anti-apoptotic Regenerative Upregulation of iNOS and IDO in MSCs; inhibition of macrophage, neutrophil, and CD4 + T-cell infiltration; reduction of TNF-α, IL-1β, IL-6 levels Enhanced immunosuppressive function of MSCs via activation of IFN-γ–Akt–iNOS/IDO pathway Improved preservation of acinar cell structure; reduced necrosis and edema Reduction of acinar apoptosis Stimulation of MSC potential for immune modulation and tissue regeneration mSe-PP [ 46 ] Selenized polysaccharide from Poria cocos Liposomes Macrophage plasma membranes Lipid nanocarriers Metalloid nanoparticles Biological and biogenic nanostructures Passive and active Antioxidant Anti-inflammatory Immunomodulatory Anti-apoptotic Reduction of intracellular ROS in RAW264.7 cells; reduced oxidative stress in vivo Decrease in TNF-α, IL-6, MCP-1; reduced macrophage and neutrophil infiltration; inhibition of AKT/mTOR pathway; restoration of autophagic flux (degradation of LC3 and p62/SQSTM1) Modulation of macrophage activity; reduction of inflammatory cytokines; reduced infiltration by CD45 + and F4/80 + cells Decrease in TUNEL-positive cells; inhibition of AKT/mTOR signaling in macrophages MPBZC [ 47 ] Prussian blue (PB) ZIF-8 shell Celastrol (CEL) Macrophage membrane (M) Metal nanoparticles Biological and biogenic nanostructures Passive and active Antioxidant Anti-inflammatory Mitochondria-targeted Immunomodulatory Cytoprotective Anti-apoptotic Regenerative Catalase-, peroxidase-, and SOD-like activity; scavenging ROS (O 2 − , H 2 O 2 , ·OH) Reduction of TNF-α, IL-6, IL-1β; reduced infiltration of inflammatory cells in tissues Activation of mitophagy (via Nur77); normalization of ΔΨm and ATP levels Upregulation of CD163 (anti-inflammatory macrophage marker) Reduction of acinar apoptosis; promotion of regeneration Decrease in apoptotic cells (TUNEL, Annexin V assay) Stimulation of acinar cell regeneration (increased Ki-67) Nanocerium [ 48 ] Cerium dioxide (CeO 2 ) Metal/metal oxide nanoparticles Passive Antioxidant Anti-inflammatory Mitochondria-targeted Cytoprotective SOD and catalase-mimicking activity; reduction of intracellular and mitochondrial ROS, MDA, NO; Nrf2 activation; increase in GSH, NQO1, SOD1 NF-κB (p65) inhibition; reduced nuclear translocation; decrease in IL-1β, IL-6, TNF-α, IL-17, COX-2; suppression of ICAM1, PECAM1 Reduction in mitochondrial superoxide (MitoSOX); normalization of ΔΨm Reduction in acinar cell necrosis, edema, infiltration nMITO [ 49 ] Mitochondria Neutrophil membranes Biological and biogenic nanostructures Passive and active Antioxidant Anti-inflammatory Mitochondria-targeted Immunomodulatory Anti-apoptotic Regenerative Reduction of ROS production Binding and neutralization of cytokines (TNF-α, IL-1β, IL-6) and chemokines (CXCL-2, CCL2, MCP-1); reduced neutrophil and macrophage migration Restoration of ΔΨm; reduced mtROS; inhibition of mPTP opening; increased ATP levels Decrease in IL-10, TNF-α, IL-12 in systemic circulation; reduced infiltration of F4/80⁺ macrophages and Ly6G⁺ neutrophils Reduction of hepatocyte and cardiomyocyte apoptosis Restoration of cellular function in various tissues (heart, liver, pancreas) SL@M@Arg-MSNs@BA [ 50 ] Silica precursor with arginine-based amide bonds Mesoporous silica nanoparticles (MSNs) Calcium chelator BAPTA-AM (BA) MSC membranes Metalloid nanoparticles Biological and biogenic nanostructures Passive and active Antioxidant Anti-inflammatory Immunomodulatory Cytoprotective Anti-apoptotic Increase in GSH, SOD; reduction in MDA, DHE Inhibition of p-IκBα/NF-κB/TNF-α/IL-6 cascade; reduced neutrophil and macrophage infiltration; reduced NETs formation Repolarization of macrophages to M2 phenotype; reduction of M1 inflammatory response Reduced necrosis Reduced TUNEL-positive cells; inhibition of CaMKII/p-RIP3/p-MLKL/caspase-8,9 signaling pathways 2 N@M@HMPB@BA#Ga [ 51 ] Prussian blue Calcium chelator BAPTA-AM Gabexate mesylate Neutrophil membranes N, N-dimethyl-1,3-propanediamine groups Metal nanoparticles Biological and biogenic nanostructures Passive and active Antioxidant Anti-inflammatory Mitochondria-targeted Immunomodulatory Cytoprotective Anti-apoptotic Anti-enzymatic Neutralization of ABTS+ radicals; reduction of ROS in cells Reduction of TNF-α, IL-6; increase in IL-10; decreased M1 macrophage polarization; stimulation of M2 phenotype Restoration of ΔΨm and reduction of mtROS Suppression of M1 inflammatory phenotype; promotion of M2 anti-inflammatory response Preservation of acinar cell viability; inhibition of necrosis Reduced caspase-dependent apoptotic activity; restoration of Beclin-1/p62/LC3; decreased ATF4/CHOP Inhibition of trypsin activity mTWNDs [ 52 ] Phosphotungstic acid Tannic acid Melanin Organometallic nanoparticles Polymeric nanocarriers Biological and biogenic nanostructures Passive and active Antioxidant Anti-inflammatory Mitochondria-targeted Immunomodulatory Anti-apoptotic Scavenging of mtROS (O 2 − , ·OH, H 2 O 2 , ONOO − ) Inhibition of macrophage activation, TNF-α, IL-1β secretion; stimulation of IL-4, IL-10 Binding to TOM20; reduction of mtROS; maintenance of ΔΨm; preservation of ATP production; prevention of mtDNA leakage Suppression of STING pathway activation in macrophages; reduced immune activation and M1 polarization Inhibition of cytochrome c release; decreased Bax expression; increased Bcl-2; reduced TUNEL+ cells CO-HbV [ 53 ] Hemoglobin Carbon monoxide (CO) Phospholipid liposomal shell Polyethylene glycol Lipid nanocarriers Passive Antioxidant Anti-inflammatory Cytoprotective Reduction of oxidative stress marker NO 2 -Tyr accumulation in pancreas, liver, kidneys, and lungs Decrease in TNF-α and IL-1β in plasma and neutrophil infiltration in tissues Reduction in acinar cell necrosis, edema, inflammation, and tissue damage in liver, kidneys, and lungs PC@PLGA [ 54 ] Polylactic-co-glycolic acid (PLGA) Hybrid membrane Polymeric nanocarriers Biological and biogenic nanostructures Active Anti-inflammatory Immunomodulatory Cytoprotective Reduction of TNF-α, IL-6, and IL-1β Activation of phagocytosis of activated neutrophils by macrophages Protection of lung and pancreatic tissue from injury by reducing edema, neutrophil infiltration, and tissue destruction COS@SiO 2 [ 55 ] Chitosan oligosaccharides (COSs) Silicon dioxide (SiO 2 ) Metalloid nanoparticles Biogenic nanostructures Passive Antioxidant Anti-inflammatory Cytoprotective Activation of Nrf2; increased SOD; reduced MPO and MDA in pancreas and lungs Reduction of IL-6, TNF-α, IL-1β levels; inhibition of NF-κB and NLRP3 inflammasome activation Reduction of damage to pancreatic and lung tissue RA-EMP [ 56 ] Empagliflozin Rebaudioside A Biogenic nanostructures Passive Antioxidant Anti-inflammatory Anti-apoptotic Reduction in MDA content; increase in glutathione (GSH) in pancreatic tissue Reduction of ICAM-1, IL-1β, IL-6, NF-κB, TGF-β, TNF-α in pancreatic tissue Reduction in the number of TUNEL-positive cells Emodin-modified exosomes [ 57 ] Biological and biogenic nanostructures Passive Anti-inflammatory Immunomodulatory Cytoprotective Reduction in IL-1β, IL-6, TNF-α expression; decreased neutrophil (Ly6G) and M1 macrophage infiltration in lungs and pancreas Inhibition of immune cell activation (neutrophils and M1 macrophages); regulation of immune-related miRNAs (miR-29a-3p, miR-15a-3p, miR-382-5p) Improvement of lung tissue structure; reduced edema, epithelial cell damage; preservation of the air–blood barrier LNP-mRNA [ 58 ] mRNA (FGF21, APOA1) Lipid nanoparticles Lipid nanocarriers Passive Antioxidant Anti-inflammatory Cytoprotective Reduced expression of SOD2 and Hmox1 after therapy Decrease in IL-1β, Ccl2, CD45⁺ and F4/80⁺ cell infiltration Reduction in necrosis, improvement in histological outcomes FA@zein-CS [ 59 ] Ferulic acid Zein Chondroitin sulfate Polymeric nanocarriers Biogenic nanostructures Passive and active Antioxidant Anti-inflammatory Mitochondria-targeted Cytoprotective ROS scavenging; upregulation of HO-1 and SOD expression; reduction of MDA Reduction in IL-1β, TNF-α, IL-6, MCP-1 levels Decrease in mitochondrial superoxide levels Protection of RAW264.7 cells from necrosis AE–IFN-γ [ 60 ] Aloe-emodin (AE) Interferon-gamma (IFN-γ) Polylactic-co-glycolic acid (PLGA) Polymeric nanocarriers Passive targeting Anti-inflammatory Immunomodulatory Cytoprotective Upregulation of IDO and PD-L1; reduction of TNF-α release Increased IDO and PD-L1 expression in MSCs Morphological and functional protection of acinar cells PBzyme [ 61 ] Prussian blue Potassium ferricyanide Organometallic nanoparticles Passive Antioxidant Anti-inflammatory Immunomodulatory Cytoprotective Anti-apoptotic Catalase- and SOD-like activity; scavenging ·OH, ·OOH, H 2 O 2 Inhibition of IL-1β, IL-6, TNF-α in serum and tissues; reduced MCP-1; downregulation of TLR4, MYD88, NF-κB/p50, p65 Modulation of TLR/NF-κB signaling cascade Reduction of necrosis; preservation of acinar cell structure Decrease in TUNEL-positive cells CO-HbV [ 62 ] Hemoglobin Carbon monoxide Phospholipid vesicles Lipid nanocarriers Passive Antioxidant Anti-inflammatory Immunomodulatory Cytoprotective Reduction in NO 2 -Tyr accumulation in pancreas and lungs Decrease in TNF-α, IL-6, IL-1β levels; increase in IL-10; inhibition of HMGB1 expression Macrophage polarization toward M2 phenotype Reduction of pancreatic and lung injury SPIO-clodronate-liposomes [ 63 ] Clodronate Iron oxide Liposomes Lipid nanocarriers Magnetosensitive nanocarriers Metal/metal oxide nanoparticles Passive Anti-inflammatory Immunomodulatory Cytoprotective Reduction in TNF-α and other proinflammatory cytokines Disruption of ATP metabolism in macrophages, leading to their depletion Reduction of kidney cell injury CeO 2 NPs + Y 2 O 3 NPs [ 64 ] Cerium oxide Yttrium oxide Metal/metal oxide nanoparticles Passive Antioxidant Mitochondria-targeted Cytoprotective Anti-apoptotic Reduction in ROS, MDA, LPO; increase in TAC, TTM; preservation of acetylcholinesterase activity Reduction in ADP/ATP ratio Increased cell viability; decreased necrosis Reduction in caspase-3 and − 9 activity SinaCurcumin® [ 65 ] Curcumin nanomicelles Lipid nanocarriers Passive Antioxidant Anti-inflammatory Cytoprotective Reduction in MPO activity Inhibition of TLR4/NF-κB pathway; reduction of TNF-α expression Reduction in acinar cell edema and leukocyte infiltration CAPE-loaded-NL [ 66 ] Caffeic acid phenethyl ester Liposomes Lipid nanocarriers Passive Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Restoration of glutathione reductase activity and GSH levels; reduction of MDA; activation of Nrf2/HO-1 pathway Reduced NF-κB p65 expression, TNF-α and NOx levels in pancreas; decreased MPO activity Histological improvement of pancreas; improved acinar cell morphology Downregulation of caspase-3 and Bax; upregulation of Bcl-2; increased Bcl-2/Bax ratio AMX-GNPs [ 67 ] Amlexanox Polylactide-co-glycolide β-1,3-glucan Polymeric nanocarriers Biological and biogenic nanostructures Active Partially passive Anti-inflammatory Immunomodulatory Cytoprotective Suppression of TNF-α, IL-1β, IL-6 secretion; inhibition of NF-κB; reduced iNOS synthesis Stimulation of macrophage repolarization from M1 to M2 phenotype Reduction in pancreatic necrosis and fibrosis MoSe 2 @PVP [ 68 ] Molybdenum diselenide Polyvinylpyrrolidone Metal/metalloid nanoparticles Polymeric nanocarriers Passive Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Catalase-, peroxidase-, SOD-, and GPx-like activity; scavenging of H 2 O 2 , O 2 ·− , ·OH, DPPH· Reduction of IL-1β, IL-6, TNF-α levels Increased survival of RAW264.7 cells Reduction of apoptosis in cellular model (Annexin V/PI assay) PAMAM [ 69 ] Polyamidoamine dendrimers Polymeric nanocarriers Passive Anti-inflammatory Immunomodulatory Cytoprotective Downregulation of IL-1β, IL-6, TNF-α, TGFβR1 in pancreatic tissue and peritoneal macrophages; inhibition of NF-κB nuclear translocation in macrophages Reduced macrophage migration (Mac-2 + cells) into pancreas Reduction of acinar cell edema, necrosis, and infiltration tFNAs [ 70 ] Tetrahedral framework nucleic acids Biogenic nanostructures Passive Anti-inflammatory Cytoprotective Anti-apoptotic Inhibition of TNF-α, IL-1β, IL-6, MPO Preservation of pancreatic, renal, hepatic, and lung cellular structures Reduction of Bax, caspase-3, and TUNEL+ cells; increase in Bcl-2 TLNS [ 71 ] Curcumin (CUR) DTPA-dianhydride Sodium bicarbonate (SBC) Sodium dodecyl sulfate (SDS) Self-assembling nanosystem Passive Anti-inflammatory Reduction of IL-6 Cu-MOF [ 72 ] Copper-based metal-organic framework Metal-organic frameworks (MOFs) Passive Antioxidant Anti-inflammatory Cytoprotective Scavenging of ROS and RNS Inhibition of TNF-α, IL-1β, IL-6, MPO Reduction of pancreatic necrosis and lung tissue injury CDs/RES@CS [ 73 ] Carbon dots Resveratrol Chitosan Biogenic nanostructures Polymeric nanocarriers Passive Antioxidant Anti-inflammatory Cytoprotective Scavenging of ROS Reduction of MDA and inflammatory cytokines Improvement of histological indicators of pancreatic damage EMO@ZIF-8/Heparin [ 74 ] Emodin Zeolitic imidazolate framework-8 (ZIF-8) Heparin Metal-organic frameworks (MOFs) Biogenic nanostructures Passive Anti-inflammatory Antioxidant Cytoprotective Reduction in pancreatic inflammatory infiltration Scavenging of ROS Preservation of acinar cell morphology and improvement in histology SinaCurcumin® [ 75 ] Curcumin nanomicelles Lipid nanocarriers Passive Antioxidant Anti-inflammatory Cytoprotective Reduction in MPO activity Inhibition of TLR4/NF-κB pathway; reduction of TNF-α expression Reduction in acinar cell edema and leukocyte infiltration MLn [ 76 ] Moringa leaf extract nanoparticles Biogenic nanostructures Passive Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Reduction of pancreatic MDA, NO, IL-6, TNF-α; elevation of GSH, catalase, SOD, and total antioxidant capacity reduction in CRP levels and neutrophil infiltration Improved histology and decreased acinar necrosis Inhibition of DNA fragmentation Ca/Fe nanozymes [ 77 ] Calcium/iron nanoparticles Metal/metal oxide nanoparticles Passive Antioxidant Anti-inflammatory Cytoprotective Mimetic activity of catalase, SOD, peroxidase; scavenging of ROS Reduction of MPO, TNF-α, IL-6, and oxidative damage in pancreatic tissue Alleviation of histological lesions and serum injury markers Nanodrugs investigated in acute pancreatitis MVs-UiO-ED [ 22 ] Emodin (ED) UiO-66-NH 2 Macrophage membranes (MVs) Organometallic nanoparticles Biological and biogenic nanostructures Anti-inflammatory Cytoprotective Immunomodulatory Reduction in α-amylase and lipase levels; binding of proinflammatory cytokines Attenuation of acinar cell damage, edema, and necrosis Binding of endotoxins and cytokines Nano-Se [ 23 ] Selenium Antioxidant Anti-inflammatory Immunomodulatory Cytoprotective Protective pro-apoptotic Reduction in MDA and NO levels; increase in total antioxidant capacity Reduction in serum IL-1β and NF-κB expression in tissues Suppression of IL-1β, NF-κB, NO production Preservation of acinar and islet architecture Decrease in Bcl-2 expression, promoting apoptosis over necrosis FA-SF-NPs [ 24 ] Ferulic acid (FA) Silk fibroin nanoparticles (SF-NPs) Neutrophil membrane coating Polymeric nanocarriers Biological and biogenic nanostructures Antioxidant Anti-inflammatory Immunomodulatory Cytoprotective Reduction in MDA, increase in SOD, GSH/GSSG, GPx Decrease in IL-1β, IL-6, TNF-α Cytokine and inflammation suppression Protection of acinar cells and reduction of histopathological damage NPs/CLT [ 25 ] Celastrol (CLT) PEG-PLGA Neutrophil membranes Polymeric nanocarriers Biological and biogenic nanostructures Anti-inflammatory Immunomodulatory Cytoprotective Reduction in TNF-α, IL-6, IL-1β, NF-κB, MPO; decreased infiltration, edema, amylase Suppression of neutrophil activity and cytokines Acinar cell protection, reduction in necrosis and infiltration BRSNPs [ 26 ] Bilirubin Silk fibroin (SF) Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Reduction of ROS and MDA; increased SOD activity; activation of Nrf2/HO-1 pathway Inhibition of NF-κB activation; reduced expression of TNF-α, ICAM-1, MPO, CD68 Protection of acinar cells from oxidative damage; reduced necrosis; improved cell viability Lowered caspase-3 levels in pancreatic tissue pHA@IBNC [ 27 ] Epigallocatechin gallate (EGCG) Interleukin-22 (IL-22) Hyaluronic acid (HA) Polymeric nanocarriers Metal/metal oxide nanoparticles Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Reduction of ROS; restoration of redox balance in pancreatic and intestinal tissues Suppression of TNF-α, IL-1β, IL-6 expression; inhibition of NF-κB activation; decreased infiltration of macrophages (CD86+), neutrophils (Ly6G+) Enterocyte cytoskeleton recovery; reduced cell stress; intestinal and acinar cell protection Reduced TUNEL-positive cells and caspase-3 expression Oc-2 M@HMnO 2 CsA [ 28 ] Manganese dioxide nanoparticles (HMnO 2 ) M2-like macrophage membranes Octreotide (Oc) Cyclosporin A (CsA) Metal/metal oxide nanoparticles Biological and biogenic nanostructures Polymeric nanocarriers Antioxidant Anti-inflammatory Mitochondria-targeted Immunomodulatory Cytoprotective Anti-apoptotic Reduction of ROS and generation of O 2 Inhibition of IL-6, IL-1β secretion and other proinflammatory cytokines; suppression of caspase-11 and GSDME-mediated pyroptosis Inhibition of mPTP opening, recovery of ΔΨm, reduced Cyt-C release, decreased mtROS Phagocytosis avoidance (CD47 signal), macrophage repolarization to anti-inflammatory phenotype (CD163⁺) Enhanced acinar cell viability, preservation of ATP and MMPs; reduction of intracellular Ca 2+ Suppression of Apaf-1 → Caspase-11 → Caspase-3 pathway, decreasing apoptosis; reduced TUNEL-positive cells CA-NPs [ 29 ] Cinnamic acid Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Reduction of MDA, GSSG/GSH ratio; increase in GSH Suppression of NF-κB and NLRP3 expression; reduced inflammatory cell infiltration Improved pancreatic morphology, restoration of acinar cell structure Decreased caspase-3, ASK1 levels; inhibition of MAPK pathway DSPE-Se-Se-MPEG@TN [ 30 ] DSPE-Se-Se-MPEG liposomes Tuftsin (TN) Perfluorooctyl bromide (PFOB) Antioxidant Anti-inflammatory Mitochondria-targeted Immunomodulatory Cytoprotective Anti-apoptotic Reduction in MDA; increase in GSH; activation of Nrf2/HO-1 pathway Decrease in IL-6, IL-1β, MPO; blockade of P2X7-NLRP3 Mitochondrial colocalization; restoration of ΔΨm; impact on PINK1/Parkin pathway Modulation of P2X7/NLRP3 Preservation of mitochondrial structures; improved cell survival Reduction of Bax and increase in Bcl-2 in pancreatic tissue MP/CP-NPs [ 31 ] Methylprednisolone Cysteine PEG nanoparticles Polymeric nanocarriers Lipid nanoparticles Anti-inflammatory Cytoprotective Reduction of TNF-α, IL-6, MPO levels Decrease in acinar cell necrosis M-CS-E-LNC [ 32 ] Emodin Mannosylated chitosan (Man-CS) Anti-inflammatory Immunomodulatory Cytoprotective Inhibition of TNF-α, IL-6, iNOS; macrophage polarization to M2 Induction of M1 to M2 macrophage transition via CPT1-dependent metabolic reprogramming Protection of acinar cells from inflammatory damage Nanoyttrium (NY) [ 33 ] Yttrium oxide (Y 2 O 3 ) Antioxidant Anti-inflammatory Mitochondria-targeted Cytoprotective Reduction in ROS, superoxide anion, MDA; increase in GSH, SOD, catalase; modulation of Nrf2/NQO1 signaling Suppression of IL-1β, IL-6, IL-17, TNF-α expression; inhibition of NF-κB activation (p65 nuclear translocation) Restoration of ΔΨm; reduced mitochondrial superoxide production Protection of acinar cells from oxidative and inflammatory injury; reduced histological signs of necrosis, edema, vacuolization FePTX@CM NPs [ 34 ] Proanthocyanidin (PYD) Pentoxifylline (PTX) Iron ions Macrophage membranes Polymeric nanocarriers Metallic nanoparticles Biological and biogenic nanostructures Antioxidant Anti-inflammatory Mitochondria-targeted Immunomodulatory Cytoprotective Anti-apoptotic Reduction of mtROS in acinar cells; blockade of mtROS-mediated Golgi stress Inhibition of IL-1β, IL-6 secretion, NF-κB activity, neutrophil recruitment Reduction of mtROS; improved mitochondrial function in acinar cells Reduction of macrophage PANoptosis by regulating Zbp1, RIPK3, Casp6 expression Decreased secretion of amylase and lipase, protecting acinar cells from autodigestion Blockade of PANoptosis (apoptosis, necroptosis, pyroptosis) especially in macrophages Se-NPs [ 35 ] Selenium Metalloid nanoparticles Biological and biogenic nanostructures Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Increased antioxidant potential; reduced MDA and NO in pancreatic tissue Decreased IL-1β levels Normalization of glycemia, insulin, and HOMA-β Reduction of Bcl-2 expression in pancreatic tissues Se@SiO 2 [ 36 ] Selenium Silicon dioxide Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Reduction of ROS, MDA, MPO; increase in GSH, SOD; activation of Nrf2/HO-1/NQO1 signaling pathway Decreased IL-6, IL-1β, TNF-α levels; inhibition of TLR4/MyD88/p-p65 (NF-κB) signaling cascade Reduced injury in pancreas, lungs, liver, and kidneys Decrease in TUNEL-positive cells MoSe 2 -PVP NPs [ 37 ] Molybdenum diselenide (MoSe2) Polyvinylpyrrolidone (PVP) Metalloid nanoparticles Polymeric carriers Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Enzymatic mimicry of CAT, SOD, POD, GPx; scavenging of H 2 O 2 , ·OH, ·O 2 − , DPPH Reduction of TNF-α, IL-1β, IL-6 levels Protection of cells from H 2 O 2 -induced cytotoxicity Reduction of apoptotic cell percentage DTM@KA NPs [ 38 ] Kaempferol Thioacetal Lipid-polymer conjugate DSPE-PEG2000 Antioxidant Anti-inflammatory Mitochondria-targeted Anti-apoptotic Reduction of ROS; increase in GSH/GSSG; activation of Nrf2/HO-1 pathway Decrease in IL-1β, IL-6, MPO, p-p65, caspase-3 Activation of TOM20–STAT6–Drp1/PINK1–Parkin pathway Increase in Bcl-2, reduction in Bax and caspase-3 MΦ-NP(L&K) [ 39 ] Melittin and MJ-33 Macrophage membranes Polymeric nanoparticles Biological and biogenic nanostructures Anti-enzymatic Anti-inflammatory Immunomodulatory Cytoprotective Anti-apoptotic Neutralization of phospholipase A2 activity Reduction of IL-6, TNF-α, IL-1β; inhibition of NF-κB activation Suppression of immune-inflammatory response via macrophage interaction Protection of acinar cells from necrosis Reduction of apoptosis in acinar cells confirmed by flow cytometry FST-loaded LPHNPs [ 40 ] Fisetin (FST) Lipid-polymer hybrid nanoparticles Passive Partially active Antioxidant Anti-inflammatory Cytoprotective Reduction of MDA and preservation of GSH in pancreatic tissues Decrease in expression of NF-κB, TLR4, IL-1β, TNF-α, IL-6, NLRP3, CRP Reduction of necrosis, edema, infiltration MU [ 41 ] Ulinastatin PEG-PLGA Macrophage membrane Polymeric nanoparticles Biological and biogenic nanostructures Anti-inflammatory Cytoprotective Immunomodulatory Reduction of IL-6 and TNF-α in serum and pancreatic tissue; inhibition of IκBα/p65/NF-κB pathway Preservation of HPDE6-C7 (normal pancreatic ductal epithelial cells) viability Immunomimicry enabling phagocytosis evasion; modulation of local immune response via cytokine interaction MSN-APT-LP [ 42 ] Silicon IL-6 aptamer Lipase Anti-inflammatory Immunomodulatory For enzyme delivery and activation Binding of IL-6 to reduce proinflammatory response IL-6 depletion mediates immunomodulation Triglyceride decomposition in plasma; reduction of lipotoxicity and pancreatic burden BAPTAAM-loaded LN [ 43 ] (BLN) BAPTA-AM Liposomal nanoparticles Antioxidant Anti-inflammatory Immunomodulatory Cytoprotective Anti-apoptotic Reduction of ROS in AR42J cells; decreased MDA; increased SOD and GSH Lower TNF-α and IL-6 in serum and RAW264.7 cells; inhibited macrophage activation; reduced cathepsin B activity Suppression of macrophage activation and cytokine release (IL-6, TNF-α) in response to LPS Protection of acinar cells from apoptosis, necrosis, autoactivation of enzymes; normalization of Ca 2+ levels Inhibition of TNF-α/cathepsin B signaling pathway IrNP-PVP [ 44 ] Iridium Polyvinylpyrrolidone Metal nanoparticles Polymeric nanocarriers Antioxidant Anti-inflammatory Mitochondria-targeted Cytoprotective Anti-apoptotic Catalase-, peroxidase-, and SOD-like activity; scavenging of H 2 O 2 , ·OH, ·O 2 − , DPPH· Reduction of TNF-α, IL-1β, IL-6 in serum and pancreatic tissue Restoration of mitochondrial structure, improvement of ΔΨm, increased activity of mitochondrial respiratory chain complexes I and IV Improved viability of RAW264.7 and HUAEC cells after LPS and H 2 O 2 exposure TUNEL and Annexin-V/PI testing confirm decreased apoptosis in cells and tissues MSC + ICT-NPs [ 45 ] Interferon-gamma Chloroquine Tamoxifen PLGA nanoparticles Polymeric nanocarriers Lipid nanocarriers Anti-inflammatory Immunomodulatory Cytoprotective Anti-apoptotic Regenerative Upregulation of iNOS and IDO in MSCs; inhibition of macrophage, neutrophil, and CD4 + T-cell infiltration; reduction of TNF-α, IL-1β, IL-6 levels Enhanced immunosuppressive function of MSCs via activation of IFN-γ–Akt–iNOS/IDO pathway Improved preservation of acinar cell structure; reduced necrosis and edema Reduction of acinar apoptosis Stimulation of MSC potential for immune modulation and tissue regeneration mSe-PP [ 46 ] Selenized polysaccharide from Poria cocos Liposomes Macrophage plasma membranes Lipid nanocarriers Metalloid nanoparticles Biological and biogenic nanostructures Antioxidant Anti-inflammatory Immunomodulatory Anti-apoptotic Reduction of intracellular ROS in RAW264.7 cells; reduced oxidative stress in vivo Decrease in TNF-α, IL-6, MCP-1; reduced macrophage and neutrophil infiltration; inhibition of AKT/mTOR pathway; restoration of autophagic flux (degradation of LC3 and p62/SQSTM1) Modulation of macrophage activity; reduction of inflammatory cytokines; reduced infiltration by CD45 + and F4/80 + cells Decrease in TUNEL-positive cells; inhibition of AKT/mTOR signaling in macrophages MPBZC [ 47 ] Prussian blue (PB) ZIF-8 shell Celastrol (CEL) Macrophage membrane (M) Metal nanoparticles Biological and biogenic nanostructures Antioxidant Anti-inflammatory Mitochondria-targeted Immunomodulatory Cytoprotective Anti-apoptotic Regenerative Catalase-, peroxidase-, and SOD-like activity; scavenging ROS (O 2 − , H 2 O 2 , ·OH) Reduction of TNF-α, IL-6, IL-1β; reduced infiltration of inflammatory cells in tissues Activation of mitophagy (via Nur77); normalization of ΔΨm and ATP levels Upregulation of CD163 (anti-inflammatory macrophage marker) Reduction of acinar apoptosis; promotion of regeneration Decrease in apoptotic cells (TUNEL, Annexin V assay) Stimulation of acinar cell regeneration (increased Ki-67) Nanocerium [ 48 ] Cerium dioxide (CeO 2 ) Antioxidant Anti-inflammatory Mitochondria-targeted Cytoprotective SOD and catalase-mimicking activity; reduction of intracellular and mitochondrial ROS, MDA, NO; Nrf2 activation; increase in GSH, NQO1, SOD1 NF-κB (p65) inhibition; reduced nuclear translocation; decrease in IL-1β, IL-6, TNF-α, IL-17, COX-2; suppression of ICAM1, PECAM1 Reduction in mitochondrial superoxide (MitoSOX); normalization of ΔΨm Reduction in acinar cell necrosis, edema, infiltration nMITO [ 49 ] Mitochondria Neutrophil membranes Antioxidant Anti-inflammatory Mitochondria-targeted Immunomodulatory Anti-apoptotic Regenerative Reduction of ROS production Binding and neutralization of cytokines (TNF-α, IL-1β, IL-6) and chemokines (CXCL-2, CCL2, MCP-1); reduced neutrophil and macrophage migration Restoration of ΔΨm; reduced mtROS; inhibition of mPTP opening; increased ATP levels Decrease in IL-10, TNF-α, IL-12 in systemic circulation; reduced infiltration of F4/80⁺ macrophages and Ly6G⁺ neutrophils Reduction of hepatocyte and cardiomyocyte apoptosis Restoration of cellular function in various tissues (heart, liver, pancreas) SL@M@Arg-MSNs@BA [ 50 ] Silica precursor with arginine-based amide bonds Mesoporous silica nanoparticles (MSNs) Calcium chelator BAPTA-AM (BA) MSC membranes Metalloid nanoparticles Biological and biogenic nanostructures Antioxidant Anti-inflammatory Immunomodulatory Cytoprotective Anti-apoptotic Increase in GSH, SOD; reduction in MDA, DHE Inhibition of p-IκBα/NF-κB/TNF-α/IL-6 cascade; reduced neutrophil and macrophage infiltration; reduced NETs formation Repolarization of macrophages to M2 phenotype; reduction of M1 inflammatory response Reduced necrosis Reduced TUNEL-positive cells; inhibition of CaMKII/p-RIP3/p-MLKL/caspase-8,9 signaling pathways 2 N@M@HMPB@BA#Ga [ 51 ] Prussian blue Calcium chelator BAPTA-AM Gabexate mesylate Neutrophil membranes N, N-dimethyl-1,3-propanediamine groups Metal nanoparticles Biological and biogenic nanostructures Antioxidant Anti-inflammatory Mitochondria-targeted Immunomodulatory Cytoprotective Anti-apoptotic Anti-enzymatic Neutralization of ABTS+ radicals; reduction of ROS in cells Reduction of TNF-α, IL-6; increase in IL-10; decreased M1 macrophage polarization; stimulation of M2 phenotype Restoration of ΔΨm and reduction of mtROS Suppression of M1 inflammatory phenotype; promotion of M2 anti-inflammatory response Preservation of acinar cell viability; inhibition of necrosis Reduced caspase-dependent apoptotic activity; restoration of Beclin-1/p62/LC3; decreased ATF4/CHOP Inhibition of trypsin activity mTWNDs [ 52 ] Phosphotungstic acid Tannic acid Melanin Organometallic nanoparticles Polymeric nanocarriers Biological and biogenic nanostructures Antioxidant Anti-inflammatory Mitochondria-targeted Immunomodulatory Anti-apoptotic Scavenging of mtROS (O 2 − , ·OH, H 2 O 2 , ONOO − ) Inhibition of macrophage activation, TNF-α, IL-1β secretion; stimulation of IL-4, IL-10 Binding to TOM20; reduction of mtROS; maintenance of ΔΨm; preservation of ATP production; prevention of mtDNA leakage Suppression of STING pathway activation in macrophages; reduced immune activation and M1 polarization Inhibition of cytochrome c release; decreased Bax expression; increased Bcl-2; reduced TUNEL+ cells CO-HbV [ 53 ] Hemoglobin Carbon monoxide (CO) Phospholipid liposomal shell Polyethylene glycol Antioxidant Anti-inflammatory Cytoprotective Reduction of oxidative stress marker NO 2 -Tyr accumulation in pancreas, liver, kidneys, and lungs Decrease in TNF-α and IL-1β in plasma and neutrophil infiltration in tissues Reduction in acinar cell necrosis, edema, inflammation, and tissue damage in liver, kidneys, and lungs PC@PLGA [ 54 ] Polylactic-co-glycolic acid (PLGA) Hybrid membrane Polymeric nanocarriers Biological and biogenic nanostructures Anti-inflammatory Immunomodulatory Cytoprotective Reduction of TNF-α, IL-6, and IL-1β Activation of phagocytosis of activated neutrophils by macrophages Protection of lung and pancreatic tissue from injury by reducing edema, neutrophil infiltration, and tissue destruction COS@SiO 2 [ 55 ] Chitosan oligosaccharides (COSs) Silicon dioxide (SiO 2 ) Metalloid nanoparticles Biogenic nanostructures Antioxidant Anti-inflammatory Cytoprotective Activation of Nrf2; increased SOD; reduced MPO and MDA in pancreas and lungs Reduction of IL-6, TNF-α, IL-1β levels; inhibition of NF-κB and NLRP3 inflammasome activation Reduction of damage to pancreatic and lung tissue RA-EMP [ 56 ] Empagliflozin Rebaudioside A Antioxidant Anti-inflammatory Anti-apoptotic Reduction in MDA content; increase in glutathione (GSH) in pancreatic tissue Reduction of ICAM-1, IL-1β, IL-6, NF-κB, TGF-β, TNF-α in pancreatic tissue Reduction in the number of TUNEL-positive cells Anti-inflammatory Immunomodulatory Cytoprotective Reduction in IL-1β, IL-6, TNF-α expression; decreased neutrophil (Ly6G) and M1 macrophage infiltration in lungs and pancreas Inhibition of immune cell activation (neutrophils and M1 macrophages); regulation of immune-related miRNAs (miR-29a-3p, miR-15a-3p, miR-382-5p) Improvement of lung tissue structure; reduced edema, epithelial cell damage; preservation of the air–blood barrier LNP-mRNA [ 58 ] mRNA (FGF21, APOA1) Lipid nanoparticles Antioxidant Anti-inflammatory Cytoprotective Reduced expression of SOD2 and Hmox1 after therapy Decrease in IL-1β, Ccl2, CD45⁺ and F4/80⁺ cell infiltration Reduction in necrosis, improvement in histological outcomes FA@zein-CS [ 59 ] Ferulic acid Zein Chondroitin sulfate Polymeric nanocarriers Biogenic nanostructures Antioxidant Anti-inflammatory Mitochondria-targeted Cytoprotective ROS scavenging; upregulation of HO-1 and SOD expression; reduction of MDA Reduction in IL-1β, TNF-α, IL-6, MCP-1 levels Decrease in mitochondrial superoxide levels Protection of RAW264.7 cells from necrosis AE–IFN-γ [ 60 ] Aloe-emodin (AE) Interferon-gamma (IFN-γ) Polylactic-co-glycolic acid (PLGA) Anti-inflammatory Immunomodulatory Cytoprotective Upregulation of IDO and PD-L1; reduction of TNF-α release Increased IDO and PD-L1 expression in MSCs Morphological and functional protection of acinar cells PBzyme [ 61 ] Prussian blue Potassium ferricyanide Antioxidant Anti-inflammatory Immunomodulatory Cytoprotective Anti-apoptotic Catalase- and SOD-like activity; scavenging ·OH, ·OOH, H 2 O 2 Inhibition of IL-1β, IL-6, TNF-α in serum and tissues; reduced MCP-1; downregulation of TLR4, MYD88, NF-κB/p50, p65 Modulation of TLR/NF-κB signaling cascade Reduction of necrosis; preservation of acinar cell structure Decrease in TUNEL-positive cells CO-HbV [ 62 ] Hemoglobin Carbon monoxide Phospholipid vesicles Antioxidant Anti-inflammatory Immunomodulatory Cytoprotective Reduction in NO 2 -Tyr accumulation in pancreas and lungs Decrease in TNF-α, IL-6, IL-1β levels; increase in IL-10; inhibition of HMGB1 expression Macrophage polarization toward M2 phenotype Reduction of pancreatic and lung injury SPIO-clodronate-liposomes [ 63 ] Clodronate Iron oxide Liposomes Lipid nanocarriers Magnetosensitive nanocarriers Metal/metal oxide nanoparticles Anti-inflammatory Immunomodulatory Cytoprotective Reduction in TNF-α and other proinflammatory cytokines Disruption of ATP metabolism in macrophages, leading to their depletion Reduction of kidney cell injury CeO 2 NPs + Y 2 O 3 NPs [ 64 ] Cerium oxide Yttrium oxide Antioxidant Mitochondria-targeted Cytoprotective Anti-apoptotic Reduction in ROS, MDA, LPO; increase in TAC, TTM; preservation of acetylcholinesterase activity Reduction in ADP/ATP ratio Increased cell viability; decreased necrosis Reduction in caspase-3 and − 9 activity SinaCurcumin® [ 65 ] Curcumin nanomicelles Antioxidant Anti-inflammatory Cytoprotective Reduction in MPO activity Inhibition of TLR4/NF-κB pathway; reduction of TNF-α expression Reduction in acinar cell edema and leukocyte infiltration CAPE-loaded-NL [ 66 ] Caffeic acid phenethyl ester Liposomes Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Restoration of glutathione reductase activity and GSH levels; reduction of MDA; activation of Nrf2/HO-1 pathway Reduced NF-κB p65 expression, TNF-α and NOx levels in pancreas; decreased MPO activity Histological improvement of pancreas; improved acinar cell morphology Downregulation of caspase-3 and Bax; upregulation of Bcl-2; increased Bcl-2/Bax ratio AMX-GNPs [ 67 ] Amlexanox Polylactide-co-glycolide β-1,3-glucan Polymeric nanocarriers Biological and biogenic nanostructures Active Partially passive Anti-inflammatory Immunomodulatory Cytoprotective Suppression of TNF-α, IL-1β, IL-6 secretion; inhibition of NF-κB; reduced iNOS synthesis Stimulation of macrophage repolarization from M1 to M2 phenotype Reduction in pancreatic necrosis and fibrosis MoSe 2 @PVP [ 68 ] Molybdenum diselenide Polyvinylpyrrolidone Metal/metalloid nanoparticles Polymeric nanocarriers Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Catalase-, peroxidase-, SOD-, and GPx-like activity; scavenging of H 2 O 2 , O 2 ·− , ·OH, DPPH· Reduction of IL-1β, IL-6, TNF-α levels Increased survival of RAW264.7 cells Reduction of apoptosis in cellular model (Annexin V/PI assay) PAMAM [ 69 ] Polyamidoamine dendrimers Anti-inflammatory Immunomodulatory Cytoprotective Downregulation of IL-1β, IL-6, TNF-α, TGFβR1 in pancreatic tissue and peritoneal macrophages; inhibition of NF-κB nuclear translocation in macrophages Reduced macrophage migration (Mac-2 + cells) into pancreas Reduction of acinar cell edema, necrosis, and infiltration tFNAs [ 70 ] Tetrahedral framework nucleic acids Anti-inflammatory Cytoprotective Anti-apoptotic Inhibition of TNF-α, IL-1β, IL-6, MPO Preservation of pancreatic, renal, hepatic, and lung cellular structures Reduction of Bax, caspase-3, and TUNEL+ cells; increase in Bcl-2 TLNS [ 71 ] Curcumin (CUR) DTPA-dianhydride Sodium bicarbonate (SBC) Sodium dodecyl sulfate (SDS) Cu-MOF [ 72 ] Copper-based metal-organic framework Antioxidant Anti-inflammatory Cytoprotective Scavenging of ROS and RNS Inhibition of TNF-α, IL-1β, IL-6, MPO Reduction of pancreatic necrosis and lung tissue injury CDs/RES@CS [ 73 ] Carbon dots Resveratrol Chitosan Biogenic nanostructures Polymeric nanocarriers Antioxidant Anti-inflammatory Cytoprotective Scavenging of ROS Reduction of MDA and inflammatory cytokines Improvement of histological indicators of pancreatic damage EMO@ZIF-8/Heparin [ 74 ] Emodin Zeolitic imidazolate framework-8 (ZIF-8) Heparin Metal-organic frameworks (MOFs) Biogenic nanostructures Anti-inflammatory Antioxidant Cytoprotective Reduction in pancreatic inflammatory infiltration Scavenging of ROS Preservation of acinar cell morphology and improvement in histology SinaCurcumin® [ 75 ] Curcumin nanomicelles Antioxidant Anti-inflammatory Cytoprotective Reduction in MPO activity Inhibition of TLR4/NF-κB pathway; reduction of TNF-α expression Reduction in acinar cell edema and leukocyte infiltration MLn [ 76 ] Moringa leaf extract nanoparticles Antioxidant Anti-inflammatory Cytoprotective Anti-apoptotic Reduction of pancreatic MDA, NO, IL-6, TNF-α; elevation of GSH, catalase, SOD, and total antioxidant capacity reduction in CRP levels and neutrophil infiltration Improved histology and decreased acinar necrosis Inhibition of DNA fragmentation Ca/Fe nanozymes [ 77 ] Calcium/iron nanoparticles Antioxidant Anti-inflammatory Cytoprotective Mimetic activity of catalase, SOD, peroxidase; scavenging of ROS Reduction of MPO, TNF-α, IL-6, and oxidative damage in pancreatic tissue Alleviation of histological lesions and serum injury markers Table 2 Overview of nanocarrier classes, targeting strategies, mechanisms, and key outcomes in experimental acute pancreatitis Nanocarrier class Representative examples Primary targeting strategy Main mechanistic actions Typical therapeutic outcomes in AP models Polymeric nanocarriers PLGA and PEG–PLGA NPs, chitosan-based systems, silk fibroin NPs, tetrahedral framework nucleic acids Passive EPR-mediated accumulation; active targeting via neutrophil or macrophage membrane cloaking and ligand decoration Delivery of anti-inflammatory and antioxidant agents; modulation of immune cells; protection of mitochondria and intestinal barrier Reduced pancreatic edema and necrosis; lower serum amylase/lipase and cytokine levels; attenuation of acute lung injury; improved survival Lipid-based nanocarriers Liposomes, solid lipid nanoparticles, nanoemulsions, hybrid lipid–polymer NPs (e.g., fisetin-loaded systems) Systemic delivery with preferential uptake by inflamed pancreas; mitochondrial targeting using pH- or ROS-responsive lipids Enhanced solubility and stability of hydrophobic drugs; inhibition of NF-κB and NLRP3 signaling; reduction of oxidative stress and Ca 2+ overload Improved pharmacokinetics; decreased pancreatic injury scores and inflammatory infiltrates; mitigation of distant organ damage Carbon-based nanostructures Carbon dots, bimetal-doped carbon dots, RES@CS and related composite nanosystems Passive targeting plus integration into multifunctional platforms with membrane coatings or polymer shells Nanozyme-like ROS scavenging; imaging-guided delivery; combined antioxidant, anti-inflammatory, and anti-enzymatic effects Improved redox balance; reduced histological damage; simultaneous diagnostic and therapeutic (theranostic) benefits Organometallic nanoparticles Metal–organic frameworks (e.g., Cu-MOFs), organometallic nanozymes and hybrid OMN platforms Mitochondria-oriented and inflammation-oriented targeting using surface ligands and biomimetic coatings Multienzyme-mimetic ROS detoxification; inhibition of DAMP-driven sterile inflammation; preservation of mitochondrial function Marked reductions in pancreatic ROS and MDA; protection of ΔΨm; decreased tissue necrosis and improved organ function Metal, metal oxide, and metalloid NPs Y 2 O 3 NPs, CeO 2 -based systems, selenium nanoparticles, Ca/Fe-based nanozymes Preferential accumulation in inflamed tissues; in some systems, additional targeting via carrier shells or membrane coatings Direct scavenging of superoxide, H 2 O 2 and hydroxyl radicals; activation of Nrf2/HO-1; modulation of ferroptosis and immune responses Lower oxidative stress markers; reduced pancreatic and intestinal injury; amelioration of ferroptosis-driven damage; improved survival indices Biological and biogenic nanostructures Cell membrane–coated NPs (neutrophil, macrophage, platelet, apoptotic cell), MSC-based systems, immunomitochondria Biomimetic homing to inflamed vasculature and pancreas; engagement of immune checkpoints and reparative pathways Cytokine sequestration; reprogramming of macrophages; delivery of functional mitochondria; enhancement of endogenous immunoregulatory signals Dampened systemic inflammation; reduced multi-organ failure; restoration of pancreatic, hepatic, pulmonary and cardiac function Overview of nanocarrier classes, targeting strategies, mechanisms, and key outcomes in experimental acute pancreatitis Fig. 2 Risk of bias assessment for individual studies Risk of bias assessment for individual studies Fig. 3 Distribution of bias risk across SYRCLE domains Distribution of bias risk across SYRCLE domains Owing to the marked heterogeneity of the included preclinical studies in terms of animal species and strains, pancreatitis induction models, nanodrug classes and compositions, dosing regimens, routes and timing of administration, comparators, outcome definitions, and assessment time points, as well as frequent incomplete numerical reporting (e.g., lack of measures of variance or sample sizes and outcomes presented only as semi-quantitative scores or graphs), we did not perform a formal meta-analysis or calculate standardized effect sizes (for example, normalized reductions in serum amylase or TNF-α levels). Instead, we conducted a structured qualitative synthesis and summarized the direction and relative magnitude of treatment effects in detailed tables and schematic figures, rather than as pooled effect estimates.

An analysis of the current literature reveals that nanotherapy opens new avenues for the treatment of AP, particularly given the complex pathogenesis of this disease and the absence of etiotropic pharmacological agents. From a broader perspective, the present work is, to our knowledge, the first systematic review dedicated specifically to nanotechnology-based interventions in experimental acute pancreatitis. Beyond simply listing individual proof-of-concept studies, we integrated data across polymeric, lipid, inorganic/metal-based, and biological or biogenic platforms and classified them according to their dominant mechanistic targets, thereby providing a pathway-oriented view of AP nanotherapy. In addition, by applying the SYRCLE tool to assess the risk of bias and to explicitly map recurrent mechanistic patterns, safety gaps, and translational bottlenecks, our review goes beyond previous narrative overviews and offers a structured framework that can guide the rational design and prioritization of future nanotherapeutic strategies in AP. A comparative graphical synthesis of nanocarrier classes, targeting strategies, and dominant mechanisms of action is shown in Fig.  16 . Fig. 16 Comparative graphical synthesis of experimental nanotherapeutics for acute pancreatitis Comparative graphical synthesis of experimental nanotherapeutics for acute pancreatitis Numerous experimental studies have demonstrated that nanotherapeutics can attenuate inflammation, suppress oxidative stress, stabilize mitochondrial function, and prevent cytotoxicity in PACs [ 41 , 44 ]. NPs exhibit multifactorial activities by combining anti-inflammatory, antioxidant, cytoprotective, and immunomodulatory effects. For example, ferulic acid nanoparticles encapsulated in silk fibroin polymers and coated with neutrophil membranes significantly reduced the levels of MDA, IL-1β, IL-6, and TNF-α while preserving the morphological integrity of PACs [ 24 ]. Similar outcomes were observed with nanoparticles containing bilirubin [ 26 ] and kaempferol [ 38 ]. However, the magnitude and robustness of these effects differ across nanocarrier classes and experimental models, complicating direct comparisons. Although exact numerical effect sizes were rarely reported in a way that would allow formal pooling, the integrated qualitative signal across studies supports a convergent protective profile of nanotherapies at biochemical, inflammatory, structural, and mitochondrial levels in experimental acute pancreatitis. Across the heterogeneous in vivo models, nanodrug-based interventions showed a broadly consistent pattern of benefit on core readouts of pancreatic and systemic injury (Fig. 17 ). In arginine-, caerulein-, and taurocholate-induced acute pancreatitis, most nanoformulations were associated with a visible reduction in pancreatic lipid peroxidation (typically reflected by lower malondialdehyde levels) [ 26 , 28 , 43 ] together with decreased serum amylase activity [ 25 , 26 , 36 ], indicating attenuation of exocrine injury. In parallel, circulating TNF-α [ 36 , 37 , 44 ] and other pro-inflammatory cytokines tended to decline relative to untreated pancreatitis, consistent with suppression of the systemic inflammatory response. Histological scoring in the original reports generally showed less edema, acinar necrosis, and inflammatory infiltrates in nanotreated animals [ 26 , 33 , 63 ], while the few studies that assessed mitochondrial function reported partial restoration of mitochondrial membrane potential in acinar cells [ 47 ]. Taken together, these observations provide a qualitative, pattern-level synthesis of the available evidence in a context where the heterogeneity and incomplete reporting of outcomes preclude a robust quantitative meta-analysis. Fig. 17 Integrated overview of nanodrug effects on key endpoints in experimental acute pancreatitis Integrated overview of nanodrug effects on key endpoints in experimental acute pancreatitis At the mechanistic level, the nanotherapeutics included in this review converge on several key pathogenic pathways of acute pancreatitis rather than acting via a single uniform mechanism. Many polymeric, lipid, organometallic, and biogenic platforms suppress NF-κB- and MAPK-driven inflammatory signaling; downregulate COX-2 and adhesion molecules; and reduce pancreatic and systemic levels of TNF-α, IL-1β, IL-6, and other cytokines, which is accompanied by decreased neutrophil and macrophage infiltration in the pancreas and lungs [ 28 – 32 , 41 , 47 , 51 – 56 , 60 – 63 ]. The second recurrent theme is the potent control of oxidative stress: a broad range of nanoencapsulated drugs and nanozymes scavenge reactive oxygen and nitrogen species, upregulate endogenous antioxidant defenses (SOD, catalase, HO-1, GSH), and lower MDA, NO, and MPO in pancreatic and extra-pancreatic tissues, thereby limiting lipid peroxidation and microcirculatory damage [ 28 – 30 , 33 , 35 – 37 , 44 , 49 , 51 , 52 , 55 , 56 , 58 , 59 , 61 , 64 ]. Several nanosystems are explicitly designed to protect mitochondria, prevent mPTP opening, preserve ΔΨm, reduce mtROS generation and cytochrome c release, and restore ATP production and Ca 2+ homeostasis in acinar cells, resulting in reduced apoptosis and necrosis [ 28 , 30 , 38 , 44 , 49 – 52 , 59 , 64 ]. In parallel, multiple platforms modulate innate immune responses by promoting macrophage repolarization toward an M2-like phenotype, dampening NET formation, and inhibiting the NLRP3 inflammasome and STING activation, thus restraining cytokine storms and remote organ injury [ 49 – 52 , 54 , 55 , 57 , 60 , 62 , 63 ]. Finally, several formulations directly interfere with pathological enzyme activation and non-canonical cell death pathways, such as neutralizing phospholipase A 2 , attenuating Ca 2+ -dependent necroptotic signaling, and suppressing PANoptosis, pyroptosis, and ferroptosis in experimental models [ 28 , 34 , 39 , 50 , 51 ]. Collectively, these mechanistic data indicate that AP-directed nanomedicine acts in a multimodal but pathway-focused manner, simultaneously targeting inflammatory cascades, oxidative stress, mitochondrial dysfunction, dysregulated cell death, and enzymatic autodigestion. From a comparative perspective, polymeric- and lipid-based nanocarriers constitute the most extensively studied platforms and provide the broadest range of mechanistic data. Polymeric nanosystems, including PLGA- and silk fibroin-based particles, consistently demonstrate reductions in biochemical markers and histological damage while improving drug stability and enabling controlled release [ 24 – 26 , 28 , 31 , 37 , 41 , 44 ]. Lipid-based carriers, such as liposomes and hybrid lipid–polymer nanoparticles, show particular advantages in solubilizing poorly bioavailable compounds (e.g., curcumin, fisetin, CAPE) and targeting mitochondria or immune cells [ 30 , 38 , 40 , 43 , 45 , 53 , 56 , 58 , 65 , 66 ]. Organometallic, metal, metal oxide, and metalloid nanoparticles, in contrast, rely predominantly on intrinsic nanozyme-like antioxidant and anti-inflammatory properties (e.g., Cu-MOFs, PB-based nanozymes, CeO 2 , Y 2 O 3 , HMnO 2 , Se-based NPs) [ 33 , 35 – 37 , 42 , 44 , 48 , 52 , 61 , 72 , 74 ]. These systems often achieve potent ROS scavenging and inflammasome inhibition but are less frequently evaluated with regard to survival or multi-organ outcomes. Carbon-based nanostructures and nucleic acid–based frameworks occupy an intermediate position, combining strong antioxidant or imaging capabilities with relatively limited, albeit promising, data on systemic effects [ 70 , 73 ]. In parallel with AP-focused research, the broader nanomedicine field is developing platforms whose design principles are directly applicable to pancreatitis. Layered double hydroxides (LDHs) have emerged as a versatile class of two-dimensional nanomaterials with excellent biocompatibility, highly tunable composition and structure, and outstanding capacity for the controlled loading and release of small molecules, nucleic acids, and proteins [ 78 ]. Their successful integration into scaffolds for bone, cartilage, vascular, and nerve regeneration demonstrates that LDHs can simultaneously provide mechanical support, scavenge reactive oxygen species, deliver bioactive agents in a spatiotemporally controlled fashion, and eventually degrade them into physiologically acceptable ions. Similarly, biomineralized copper carbonate nanoparticles have been engineered as robust carriers for the co-delivery of glucose oxidase, nucleic acids, and chemotherapeutics, enabling pH-responsive drug release and synergistic combinations of starvation therapy, gene therapy, and chemodynamic therapy in tumor models [ 79 ]. These multimodal platforms reinforce the feasibility of assembling AP nanodrugs that combine enzyme modulation, anti-inflammatory signaling, and organ-protective effects within a single construct, rather than relying on single-mechanism formulations. Biological and biogenic nanostructures, particularly cell membrane–coated and exosome-like systems, provide some of the most sophisticated targeting strategies. Biomimetic nanoparticles that exploit macrophage or neutrophil membranes, as well as complex constructs such as MPBZC or nMITO, consistently achieve high accumulation in inflamed pancreatic tissue, prolonged circulation, and simultaneous modulation of several key pathways, including oxidative stress, autophagy/mitophagy, and immune cell recruitment [ 22 , 24 – 26 , 34 , 46 , 47 , 49 , 52 , 57 , 67 , 74 ]. When outcomes from different classes are juxtaposed, membrane-coated and actively targeted formulations generally report larger and more coherent effect sizes across multiple endpoints (biochemical markers, histology, and remote organ injury) than do non-targeted polymeric or inorganic cores. Nevertheless, these observations are derived from indirect comparisons, as genuine head-to-head studies between different nanocarrier classes under identical experimental conditions are largely lacking. Consequently, any hierarchy of “superior” platforms remains provisional. Across the included experiments, most polymeric and lipid-based nanocarriers constructed from biocompatible polymers or clinically used lipids achieved substantial attenuation of pancreatic injury at doses that did not produce overt systemic toxicity, as reflected by preserved body weight, the absence of histological damage in major non-pancreatic organs, and largely unchanged liver and kidney function tests compared with vehicle or free-drug controls [ 24 – 26 , 28 , 30 , 31 , 37 , 38 , 40 , 41 , 43 – 45 , 53 , 56 , 58 , 65 , 66 ]. Metal- and metal oxide–based nanozymes frequently produce pronounced multi-organ protection, but their long-term biodistribution and chronic toxicity have rarely been evaluated in detail, leaving their true safety margin insufficiently defined [ 33 , 35 – 37 , 42 , 44 , 48 , 52 , 61 , 72 , 74 ]. Biological and biogenic nanostructures, including cell membrane–coated particles and phytogenic nanosystems, also show sizeable therapeutic effects without obvious short-term safety signals in the reported models, although these observations are derived from a relatively small number of short-term experiments and lack head-to-head comparisons with other platforms [ 22 , 24 – 26 , 34 , 46 , 47 , 49 , 52 , 57 , 67 , 74 ]. Taken together, the currently available data support acceptable short-term safety at efficacious doses for several polymeric, lipid, metallic, and biological platforms, but do not yet al.low a robust, quantitative comparison of therapeutic indices across classes. From a clinical standpoint, the targeted delivery capability of nanoparticles is particularly valuable. Owing to the distinct vascular characteristics of inflamed pancreatic tissue, including increased permeability and impaired lymphatic drainage, nanoparticles preferentially accumulate in the affected area, bypassing systemic circulation [ 25 ]. This localized distribution enables dose reduction, minimizes systemic adverse effects, and enhances the therapeutic efficacy. For example, PLGA-based nanoparticles coated with macrophage membranes and loaded with ulinastatin exhibited a high affinity for inflamed pancreatic tissue and led to reduced expression of proinflammatory cytokines in situ [ 41 ]. Similarly, several biomimetic and ligand-decorated systems improved pancreatic and extra-pancreatic outcomes more consistently than their non-targeted counterparts [ 22 , 25 , 32 , 46 , 54 ]. However, the lack of standardized dosing regimens and follow-up durations means that the relative clinical relevance of these gains remains unclear. In addition to their anti-inflammatory and antioxidant effects, several nanotherapeutic platforms have addressed other critical mechanisms that are implicated in AP pathogenesis. Mitochondria-targeted nanoparticles have been shown to prevent mitochondrial dysfunction, which is a major contributor to acinar cell injury. For example, DSPE-Se-Se-MPEG@TN, a nanosystem containing tuftsin, decreased mtROS generation, stabilized ΔΨm, inhibited P2X7–NLRP3 inflammasome activation, reduced Bax expression, and increased Bcl-2 levels [ 30 ]. Similarly, Oc-M2M@HMnO 2 -CsA nanocomplexes demonstrated synergistic effects by inhibiting IL-1β and IL-6 secretion, reducing intracellular Ca 2+ levels, and suppressing apoptosis in acinar cells by blocking the Apaf-1 → Caspase-11 → Caspase-3 cascade [ 28 ]. Other formulations have focused on neutralizing digestive enzymes, modulating immunometabolism, or preventing regulated cell death (PANoptosis, ferroptosis, and pyroptosis), thereby targeting relatively novel mechanisms of injury [ 28 , 34 , 39 , 77 ]. However, for many of these mechanisms, the depth of functional validation (e.g., inclusion of genetic knockdown controls and rescue experiments) remains limited, and in some studies the reported improvements were confined to surrogate biomarkers without clear translation into robust histological or survival benefits. Beyond nanomedicine, recent data underscore the potential of multitarget phytochemical formulations as adjunctive therapies for AP. A systematic review and meta-analysis of randomized and quasi-randomized trials assessing Xuebijing injection, a standardized injectable preparation comprising five botanical components, reported significant improvements in oxygenation index, respiratory rate, APACHE II score, and inflammatory biomarkers in patients with AP complicated by acute lung injury or acute respiratory distress syndrome as well as reductions in the incidence of respiratory failure [ 80 ]. Although most studies were small, single-center, and at risk of bias, these findings suggest that broad-spectrum anti-inflammatory, antioxidant, and immunomodulatory strategies can mitigate the systemic complications of AP. Conceptually, such multicomponent herbal formulations and nanotherapeutics share several mechanistic targets, including attenuation of cytokine storms, reduction of oxidative stress, and preservation of endothelial and epithelial barrier integrity. This raises the intriguing possibility that rational combinations or hybrid nanoformulations encapsulating defined herbal constituents may further enhance their efficacy while maintaining an acceptable safety profile. Importantly, AP is not a single homogeneous entity but rather comprises etiologically and mechanistically distinct clinical phenotypes, including biliary, alcohol-associated, hypertriglyceridemic, and post-ERCP forms. These phenotypes differ in their relative dominance of intraductal enzyme activation, systemic lipotoxicity, microcirculatory failure, and oxidative stress. The experimental models used in the nanotherapy literature recapitulate these mechanisms only partially: taurocholate infusion approximates necrotizing biliary AP, whereas hyperlipidemia-based models better mimic hypertriglyceridemic disease. Direct evidence for phenotype-specific differences in nanotherapeutic efficacy is still sparse because none of the included studies systematically compared the same nanosystem across different AP etiologies. Nevertheless, there are emerging examples of phenotype-oriented design. Mesoporous silica nanoparticles carrying IL-6 aptamers and lipase were explicitly developed for hyperlipidemic AP, where they simultaneously hydrolyzed circulating triglycerides and neutralized IL-6 signaling, thereby attenuating both metabolic and inflammatory injury [ 42 ]. Enzyme-directed platforms, such as PLA 2 “lure-and-kill” macrophage-membrane-coated nanoparticles and PANoptosis-targeted FePTX@CM nanocomposites, conceptually align more closely with enzyme-activation–dominant phenotypes, such as biliary or post-ERCP AP, in which abrupt ductal obstruction and massive zymogen activation precipitate acinar necrosis and sterile inflammation [ 34 , 39 ]. By contrast, OMN-based nanozymes and mitochondria-targeted systems that primarily quench ROS and restore bioenergetics (e.g., Cu-MOFs, mTWNDs, HMnO 2 nanoparticles) may be particularly attractive for oxidative-stress–driven phenotypes, including hypertriglyceridemic and alcohol-related AP [ 28 , 52 , 72 ]. Taken together, these mechanistic correspondences support the positioning of nanomedicine as a platform for precision therapy in AP, where the choice of nanocarrier and payload is matched to the patient’s etiologic and molecular profile rather than being applied uniformly to all cases. Simultaneously, the etiological spectrum of AP is being reshaped by the widespread introduction of targeted antidiabetic and anticancer therapies. A recent systematic analysis of reported sodium–glucose cotransporter-2 inhibitor (SGLT2i)-related AP cases found that empagliflozin, canagliflozin, and dapagliflozin were most frequently implicated, with a typical onset within the first few weeks of treatment and complete clinical recovery after drug withdrawal and supportive care [ 81 ]. Similarly, the synthesis of pembrolizumab-induced AP cases predominantly described mild-to-moderate presentations with pancreatic enzyme elevation and characteristic imaging features, most of which responded to discontinuation of immune checkpoint blockade and corticosteroid-based immunosuppression [ 82 ]. These observations highlight an expanding group of drug-induced forms of AP in patients with type 2 diabetes, malignancies, and other comorbidities that are typical candidates for advanced nanomedicine. Therefore, future translational work should explicitly evaluate whether nanoparticle-based interventions modify the risk, clinical course, or recovery pattern of such drug-related AP and whether prior or concomitant exposure to nanodrugs alters individual susceptibility to pancreatic injury. A more critical appraisal of the evidence also highlights several inconsistencies and areas of uncertainty. First, a substantial proportion of studies reported partial or selective improvements, such as reductions in serum amylase/lipase or specific cytokines, without proportional amelioration of histological injury or remote organ dysfunction. Second, numerous experiments have employed prophylactic or near-simultaneous administration of nanoparticles at or before AP induction, which may overestimate the therapeutic potential relative to clinically realistic scenarios in which treatment starts after disease onset. Third, negative or neutral results are rarely presented in detail, thereby introducing the risk of publication bias. Collectively, these issues limit the interpretation of the apparent superiority of specific nanocarrier classes and/or mechanisms. Particular attention has been paid to biomimetic nanoparticles that exploit immune cell membranes for inflammation-targeted delivery. These systems not only improve delivery efficiency but also scavenge circulating pathogenic factors. For example, macrophage membrane–coated nanoparticles containing melittin and MJ-33 utilize a “lure-and-kill” mechanism by binding and neutralizing phospholipase A 2 (PLA 2 ), a key enzyme in AP progression [ 39 ]. A comparable strategy was employed using peptide-functionalized nanoparticles that suppressed cytokine release and prevented acinar cell necrosis. Compared with simpler polymeric or metal-based nanozymes, such complex biomimetic carriers appear to provide broader and more durable protection; however, they also raise concerns regarding manufacturing complexity, batch-to-batch variability, and regulatory feasibility. Recent mechanistic work has also illustrated how nanotechnology can interface with emerging regulated cell death and immunomodulatory pathways relevant to AP. In lung adenocarcinoma models, downregulation of coatomer protein complex I subunit zeta 1 (COPZ1) has been shown to enhance NCOA4-mediated ferritinophagy, increase labile iron and lipid peroxidation, and trigger ferroptotic cell death [ 83 ]. Given that ferroptosis contributes to acinar cell injury and remote organ damage in experimental AP, nanoparticles engineered to fine-tune iron metabolism, ferritin turnover, or lipid peroxidation may provide a means to precisely modulate ferroptotic pathways, either to promote the resolution of inflammation or to avoid inadvertent amplification of tissue injury. In addition, macrophage-targeted nanomedicine has demonstrated efficacy across a range of chronic inflammatory conditions, including atherosclerosis, rheumatoid arthritis, and metabolic diseases, by exploiting the inherent phagocytic capacity and polarization plasticity of macrophages [ 84 ]. Ligand-modified or membrane-camouflaged nanoparticles can reprogram proinflammatory M1 macrophages toward reparative phenotypes and reshape cytokine networks, a strategy that appears particularly attractive for modulating both the early systemic inflammatory response and the later phase of immune dysregulation in AP. Finally, advances in green and biogenic synthesis, exemplified by plant extract–mediated fabrication of CuFe 2 O 4 /reduced graphene oxide nanocomposites and microbial exopolysaccharide-directed production of metal nanoparticles, as well as snail-mucus–mediated Fe 2 O 3 nanoparticles, medicinal plant leaf-derived AgNPs, and mushroom extract–based ZnONPs with combined antibacterial, antioxidant, and anticancer properties [ 85 – 89 ], suggest that eco-friendly production routes can yield multifunctional metal and metal oxide nanomaterials with favorable biocompatibility. Such platforms may facilitate the scaling up of nanodrugs for AP, reduce the need for toxic reagents in their synthesis, and improve safety profiles in the clinically fragile populations affected by severe pancreatitis. Despite compelling in vivo findings, most nanotherapeutics for AP remain in the preclinical stage. Although their advantages, including controlled release, enhanced bioavailability, multifunctional actions, and reduced systemic toxicity, are well-documented, several limitations persist. First, clinical data on nanoparticle efficacy in patients with AP are either lacking or limited. Most research has been conducted in rodent models, which do not fully replicate the complex pathophysiology of human pancreatitis [ 16 ]. Second, the synthesis of multicomponent nanosystems, particularly biomimetic or organelle-targeted structures, remains technically challenging, hindering the transition from laboratory prototypes to large-scale production [ 17 ]. Furthermore, the pharmacokinetic and toxicological profiles of many nanomaterials require thorough characterization. Metallic and metalloid-based nanoparticles (e.g., those containing iridium, selenium, or manganese oxides) may accumulate in organs, disrupt metabolic processes, or elicit unpredictable immune responses, raising concerns regarding their long-term safety [ 44 ]. Another critical issue is the effect of nanotherapeutics on the immune system. Although many nanoplatforms exhibit immunomodulatory activity, there remains a potential risk of immune dysregulation, especially with chronic or repeated administration. Certain nanostructures, such as Se@SiO 2 or various selenium- and metal-based nanoforms, have been shown to affect cytokine production, modulate key transcription factors (e.g., NF-κB and Nrf2), and alter apoptotic signaling pathways [ 35 , 37 , 46 ]. These findings highlight the need for careful immunological assessments in clinically relevant models and dedicated toxicology studies, particularly for platforms intended for systemic and repeated use. In addition, the heterogeneous nature of AP, with respect to both etiology and disease severity, demands an individualized therapeutic approach. Personalized nanotherapy tailored to a patient’s clinical phenotype and dominant pathogenic profile (e.g., oxidative stress, calcium dysregulation, or autophagic impairment) may be central to future treatment strategies. For example, BAPTA-AM–loaded liposomes have been shown to reduce intracellular calcium overload and mitigate calcium-mediated injury, whereas other systems such as DTM@KA NPs primarily target mitochondrial homeostasis [ 38 , 43 ]. It is likely that no single nanoplatform will be universally optimal; rather, the therapeutic benefit may depend on matching a given nanosystem to the prevailing pathogenic mechanism in specific AP phenotypes, such as biliary, hypertriglyceridemic, alcohol-associated, or post-ERCP pancreatitis. In this context, nanotechnology is best viewed as a toolbox for precision therapy in AP, in which nanocarrier design and payload selection are tailored to the dominant drivers of injury in a given patient, rather than being applied as a uniform strategy across all etiologies. From a translational standpoint, the gap between experimental nanotherapies and clinically usable products is determined not only by efficacy, but also by regulatory classification and quality requirements. In practice, the regulatory status of AP-targeted nanoplatforms will follow the general principles applied to nanomedicines, with classification driven by the principal intended mode of action and whether the active component is a small molecule, biological, or functional material. For most systems described in this review, such as drug-loaded polymeric or lipid nanoparticles, catalytic nanozymes with antioxidant or anti-inflammatory activity, and biomimetic vesicles, the expected pathway is that of a medicinal product (small-molecule drug or biological), with the nanocarrier or catalytic core considered part of the drug product or, in some cases, as a combination product rather than a stand-alone device. Only platforms with predominantly physical therapeutic actions (e.g., extracorporeal nanofilters for blood purification) are likely to be regulated in a device-like framework. Given the hybrid and multifunctional nature of next-generation nanozymes and biomimetic carriers, early engagement with regulators and harmonization of classification criteria across jurisdictions is crucial to avoid delays in clinical translation. These technical and regulatory constraints directly influence the cost of goods and may limit the feasibility of translating highly complex nanosystems into routine clinical use, particularly in resource-constrained settings. Accordingly, early integration of quality-by-design principles, robust in-process controls, and structured dialogue with regulatory agencies will be essential for any AP-targeted nanodrug that is to progress beyond proof-of-concept studies [ 90 – 92 ]. The second key barrier is the demonstration of safe and predictable biodistribution, clearance, and long-term safety. Even within the experimental AP literature, metal- and metalloid-based nanozymes and ultrasmall inorganic particles can accumulate in organs and modulate immune and redox pathways, raising concerns about chronic toxicity and unintended immunomodulation that must be systematically addressed before clinical use [ 35 , 37 , 44 , 46 ]. Similar safety questions have been highlighted for catalytic nanozymes and other redox-active nanomaterials in broader nanomedicine research, leading to calls for standardized assays for complement activation, cytokine release, off-target organ deposition, and biodegradation kinetics [ 93 , 94 ]. Manufacturing, costs, and regulatory compliance add an additional layer of complexity. Many of the most promising platforms in AP, including biomimetic, multicomponent, and stimuli-responsive carriers, require sophisticated, multistep production processes and tight control of physicochemical attributes (size distribution, surface charge, ligand density, membrane protein composition, catalytic activity) to ensure batch-to-batch reproducibility [ 22 – 28 , 47 ]. Scaling such processes to the Good Manufacturing Practice (GMP) level is non-trivial and has been identified as a major hurdle for next-generation nanomedicines in general [ 92 , 95 , 96 ]. These technical and regulatory constraints directly influence the cost of goods and may limit the feasibility of translating highly complex nanosystems into routine clinical use, particularly in resource-constrained settings. Therefore, early integration of quality-by-design principles, robust in-process controls, and structured dialogue with regulatory agencies will be essential for any AP-targeted nanodrug that is to progress beyond proof-of-concept studies. In summary, the successful translation of nanotherapy for AP will depend on three parallel advances: (i) better alignment of preclinical models and endpoints with human disease; (ii) systematic characterization of biodistribution, clearance, and immunological safety for each nanoplatform; and (iii) early adaptation to the appropriate regulatory pathway, including GMP-compliant, scalable, and economically viable manufacturing. In conclusion, nanotherapy is a promising and innovative strategy for the treatment of acute pancreatitis. The diversity of nanoplatforms, ranging from polymeric and lipid-based carriers to organic, inorganic, and biomimetic systems, offers a multifaceted approach to modulating the core pathogenic mechanisms of the disease. These technologies enable high local drug concentrations, minimize systemic exposure, and facilitate precise targeted drug delivery. At the same time, the current evidence is characterized by heterogeneity of models, endpoints, and methodological quality, which precludes the formal ranking of nanocarrier classes and calls for cautious interpretation. To transition from bench to bedside, comprehensive preclinical studies with standardized models and clinically relevant endpoints are needed to assess pharmacokinetics, immunogenicity, and biosafety, followed by well-designed randomized clinical trials. Only then will it be possible to establish effective and safe nanodrugs as part of the therapeutic arsenal for acute pancreatitis.

Nanotherapy for acute pancreatitis is a highly promising but still early-stage field. In this systematic review, we synthesized evidence from experimental models and a limited number of clinical studies to evaluate how polymeric, lipid-based, inorganic/metal-based, and biological or biogenic nanoplatforms modulate key pathogenic pathways of acute pancreatitis. Across heterogeneous in vivo models, nanoformulations consistently attenuated pancreatic edema, necrosis, and inflammatory infiltration; lowered serum amylase and lipase as well as proinflammatory cytokines; mitigated remote organ injury, particularly acute lung injury; and, in several severe models, improved survival compared with non-nano or untreated controls. Mechanistically, the most effective nanotherapeutic strategies converged on the suppression of inflammatory and oxidative cascades, preservation of mitochondrial function and calcium homeostasis, stabilization of microcirculation, and modulation of dysregulated cell death and immune responses. At the same time, our analysis highlights substantial limitations that preclude firm conclusions regarding comparative efficacy or direct clinical applicability. The existing evidence base is fragmented, relies on a limited set of experimental models, rarely addresses specific clinical phenotypes or drug-induced forms of acute pancreatitis, and is characterized by a moderate to serious risk of bias, incomplete reporting of pharmacokinetics and biodistribution, and scarce data on long-term toxicity and immunological safety. Clinical experience with nanotechnology-based interventions in acute pancreatitis remains restricted to small, early-phase trials. Taken together, these findings suggest that rationally designed nanotherapeutics may, in the future, become valuable adjuncts to established etiological and supportive treatments for acute pancreatitis; however, their successful translation will require rigorously designed, standardized preclinical studies, detailed safety evaluations, and carefully conducted clinical trials.

From a clinical translation standpoint, the field of nanotherapy for acute pancreatitis is still in its early stages. No nanomedicine is currently approved specifically for the treatment of AP, and standard care continues to rely on optimized fluid resuscitation, analgesia, early enteral nutrition, and the timely management of local and systemic complications. To date, the only human data come from a single small randomized placebo-controlled trial of nano-curcumin supplementation in patients with mild-to-moderate AP, which suggested potential reductions in gastrointestinal ward length of stay and analgesic requirements without major safety concerns [ 75 ]. However, this study was underpowered, short in duration, and limited to less severe disease; therefore, it cannot be considered definitive evidence of clinical benefit. Beyond the scarcity of clinical data, multifunctional nanozymes, biomimetic vesicles, and other complex nanosystems face substantial regulatory and translational hurdles, which must be appropriately classified according to their principal mode of action; satisfy stringent quality, safety, and manufacturing requirements; and demonstrate predictable pharmacokinetics, biodistribution, immunogenicity, and long-term toxicity in relevant models. These regulatory challenges, together with the limitations of current preclinical models and the difficulty in linking experimental endpoints to clinically meaningful outcomes, constitute major translational gaps that must be addressed before AP-targeted nanotherapeutics can be credibly advanced into phase I–II clinical trials. Despite the promising outcomes of preclinical studies, nanotherapy for AP has several limitations. First, the vast majority of studies have been conducted using animal models, which only partially mimic the complex pathophysiology of human pancreatitis. Second, the intricate, multicomponent nature of many nanosystems, particularly those that are biomimetic or organelle-targeted, presents significant challenges for reproducibility and large-scale manufacturing. Third, the pharmacokinetics, biodistribution, and long-term safety of various nanomaterials remain poorly characterized. In particular, metal-based nanoparticles may accumulate in organs and elicit unpredictable immune reactions, raising concerns about their chronic toxicity and systemic effects. Fourth, the potential immunomodulatory effects of nanodrugs could result in local or systemic immune dysregulation, especially with prolonged or repeated administration. A major limitation of the current evidence is the heterogeneity and inherent imperfections of preclinical models of AP. The most commonly used induction methods, cerulein hyperstimulation, retrograde infusion of sodium taurocholate into the biliopancreatic duct, high-dose L-arginine, and hyperlipidemia-based models, reproduce only selected fragments of human disease and do so in very different ways. Cerulein typically induces a relatively mild, largely reversible edematous pancreatitis with limited necrosis, whereas taurocholate produces a rapidly evolving necrotizing pancreatitis with prominent vascular injury and biliary reflux, and L-arginine causes a toxic, metabolically driven form of acinar cell death that has no direct clinical analog. In turn, hypertriglyceridemia models emphasize systemic lipid toxicity and microcirculatory disturbances. Since many nanotherapeutics are tested in a single induction model, often without justification for that choice, it is unclear whether the reported benefits are specific to a particular pattern of injury or can be extrapolated to other etiologies and severities of AP. In addition, dosing regimens and the timing of nanoparticle administration are highly inconsistent, with doses ranging over several orders of magnitude. Routes of delivery (intravenous, intraperitoneal, oral) are frequently selected for convenience rather than translational plausibility, and treatment is often administered prophylactically or at the moment of AP induction rather than after the establishment of clinically manifest disease. Only a minority of studies include any form of dose–response evaluation or pharmacokinetic justification, which limits the interpretability and clinical relevance of the “effective” doses reported. Similarly, the endpoints are heterogeneous. Many experiments rely predominantly on early surrogate markers, such as serum amylase/lipase and short-term (24–48 h) histological scores, whereas more clinically meaningful outcomes, including survival, extra-pancreatic organ dysfunction, longer-term resolution of inflammation, and prevention of fibrosis, are assessed inconsistently. This diversity of models, dosing strategies, and endpoints not only precludes quantitative synthesis but also makes it difficult to determine whether one nanocarrier class is truly superior to another or whether apparent advantages simply reflect differences in experimental design rather than intrinsic therapeutic efficacy. In addition, the marked heterogeneity of AP in terms of etiology, disease severity, and molecular pathogenesis undermines the feasibility of universal therapeutic solutions. Therefore, a one-size-fits-all approach is not likely to be effective. A promising avenue for future research is the development of personalized nanotherapeutic strategies tailored to individual clinical phenotypes and prevailing pathogenic mechanisms in each patient. For example, nanodrugs carrying calcium chelators such as BAPTA-AM are particularly suitable for patients in whom dysregulated calcium signaling and intracellular overload predominate, whereas other systems, such as kaempferol-based nanoparticles, are better suited for restoring mitochondrial function and redox homeostasis. Several prerequisites must be met to enable the clinical translation of nanotherapy in AP. These include extensive preclinical studies to elucidate mechanisms of action, determine pharmacokinetics and biodistribution, and assess immunogenicity and long-term safety profiles. In parallel, well-designed, multicenter randomized clinical trials are necessary to confirm therapeutic efficacy, optimal dosing, and safety in human populations. Only through this systematic and rigorous approach can nanotherapeutics evolve into safe, effective, and standardized interventions that may eventually be integrated into routine clinical practice for the management of acute pancreatitis.

Acute pancreatitis (AP) is a sudden-onset inflammatory disorder of the pancreas characterized by intraorgan activation of digestive enzymes and subsequent autolysis of the pancreatic parenchyma. This pathophysiological process elicits a robust local inflammatory response, which may progress to systemic inflammatory response syndrome (SIRS) in severe cases, eventually resulting in multi-organ dysfunction [ 1 ]. The etiology of AP is multifactorial. The most frequent cause is gallstone disease and associated infections or inflammatory conditions of the biliary tract, accounting for more than 40% of all cases [ 2 ]. Other major causes include excessive alcohol consumption, hypertriglyceridemia, invasive endoscopic procedures such as endoscopic retrograde cholangiopancreatography (ERCP), abdominal trauma or surgery, and drug-induced pancreatic injury (e.g., hydrochlorothiazide or sulfonamides) [ 3 ]. AP is a complex condition that involves multiple intracellular disturbances that initiate a cascade of tissue damage. The central pathogenic mechanisms include aberrant calcium signaling, mitochondrial dysfunction, premature trypsinogen activation, endoplasmic reticulum (ER) stress, failure of the unfolded protein response (UPR), and impaired autophagy [ 4 – 6 ]. Mitochondrial dysfunction plays a pivotal role in ATP depletion, increased oxidative stress, and disrupted energy homeostasis, which in turn induce ER stress and dysregulation of autophagy [ 7 , 8 ]. Key cellular changes underlying AP include premature enzymatic activation (especially of trypsinogen), excessive cytosolic calcium accumulation, mitochondrial depolarization, autophagic dysfunction, and endoplasmic reticulum (ER) stress. These processes collectively trigger inflammatory cascades, microcirculatory disturbances, and immune cell infiltration into pancreatic tissue [ 9 ]. Despite extensive research into its underlying mechanisms, the pathogenesis of AP remains unclear. The diversity of etiologic factors and clinical presentations poses diagnostic challenges and complicates the development of effective therapeutic strategies. Currently, no etiotropic treatment is available for AP. Therapeutic approaches are largely supportive and aimed at mitigating complications [ 10 , 11 ]. The main components of care include intravenous fluid resuscitation, effective analgesia, nutritional support, and prophylactic or therapeutic antibiotics when pancreatic infection is suspected [ 12 ]. Surgical intervention is typically reserved for patients with infected pancreatic necrosis or other severe complications [ 3 , 13 ]. To date, no drug has demonstrated direct efficacy in reversing or preventing AP. Most of these therapies are symptomatic [ 14 ]. Their effectiveness is frequently limited by poor bioavailability in inflamed pancreatic tissues due to edema, ischemia, and microvascular dysfunction. Systemic drug administration often results in significant toxicity and other adverse effects. Moreover, given the multifactorial nature of AP pathogenesis, no single pharmacological agent can comprehensively target al.l the pathological processes involved [ 15 ]. These findings underscore the urgent need for novel therapeutic strategies capable of precise delivery of active agents to the sites of pancreatic injury. Such targeted approaches could minimize systemic side effects, enhance local drug efficacy, and improve clinical outcomes, particularly in patients with severe AP. Nanotechnology offers a promising platform for implementing targeted therapy [ 16 , 17 ]. Owing to their unique physicochemical properties, nanomaterials can selectively accumulate in inflamed or necrotic pancreatic tissue. This enables high local drug concentrations while sparing unaffected tissues and reducing systemic toxicity, thereby improving the therapeutic safety profile [ 18 ]. Additionally, nanocarriers can protect pharmacologic agents from degradation, thereby prolonging their bioactivity. Nanotechnology also opens new avenues for diagnostics, enabling the development of highly sensitive and specific tools for early detection of AP and its complications [ 19 , 20 ]. The objective of this systematic review was to provide a comprehensive analysis of current research and future directions regarding the use of nanotechnology in the treatment of AP. This review summarizes the key types of nanocarriers, their therapeutic advantages, and their capacity to target the central mechanisms of AP pathogenesis.

Nanodrugs can accumulate in inflamed tissues via the EPR effect and can be further engineered for the active targeting of specific cells or molecules. This enables the direct delivery of anti-inflammatory, antioxidant, and other therapeutic agents to the injured pancreas, thereby increasing local efficacy and limiting systemic toxicity. In addition, certain nanomaterials possess intrinsic therapeutic properties such as antioxidant and immunomodulatory activities. Together, these features allow nanotherapy to attenuate key pathophysiological manifestations of AP, including inflammation, oxidative stress, cell death, and the premature activation of pancreatic digestive enzymes. A schematic overview of the major pathogenic cascades in acute pancreatitis and the principal points of intervention for each nanocarrier class is presented in Fig.  9 . Fig. 9 Schematic overview of pathogenic pathways in acute pancreatitis and principal points of intervention for nanotherapeutic strategies Schematic overview of pathogenic pathways in acute pancreatitis and principal points of intervention for nanotherapeutic strategies Inflammation is a central pathogenic mechanism in AP, and a large proportion of nanodrugs are primarily designed to dampen this response. Their anti-inflammatory effects can be broadly grouped into three strategies: (i) increasing pancreatic exposure to anti-inflammatory agents, (ii) modulating immune cell behavior, and (iii) inhibiting key inflammatory signaling pathways or neutralizing soluble mediators. Many formulations encapsulate natural anti-inflammatory compounds, such as celastrol, emodin, curcumin, fisetin, or caffeic acid phenethyl ester, and release them preferentially within inflamed pancreatic tissues. This enhances local drug concentrations and reduces systemic exposure while simultaneously suppressing upstream signaling through receptors such as TLR4 and transcription factors such as NF-κB and NLRP3. As a result, the downstream production of proinflammatory cytokines (IL-1β, IL-6, TNF-α) and chemokines is diminished, and leukocyte recruitment to the pancreas is attenuated [ 40 , 65 , 66 ]. Biomimetic UiO-66-based nanoparticles coated with macrophage membranes and loaded with emodin further enhance this strategy by acting as circulating “sinks” for cytokines while homing to inflamed pancreatic tissue, thereby reducing both the local and systemic inflammatory burden [ 22 ]. Neutrophil-mimicking celastrol-loaded nanocapsules accumulate at inflammatory foci, inhibit NF-κB activation, and lower serum cytokine levels, resulting in reduced pancreatic edema and neutrophil infiltration [ 25 ]. The second major axis of anti-inflammatory action is the direct targeting and reprogramming of macrophages, which are key orchestrators of AP-associated inflammation. Mannose-modified chitosan–lipid nanocapsules carrying emodin exploit mannose receptor–mediated uptake by pancreatic macrophages, decrease iNOS expression, reduce TNF-α and IL-6 production, and drive polarization toward an anti-inflammatory M2 phenotype [ 32 ]. β-Glucan-functionalized polymeric nanoparticles engage Dectin-1 on M1 macrophages, suppress NF-κB signaling, and limit IL-1β, IL-6, and TNF-α secretion, thereby further shifting the macrophage balance toward a reparative profile [ 67 ]. In a TLCS-induced mouse model of severe acute pancreatitis, an acinar cell–dual-targeted, neutrophil-membrane-camouflaged and 2 N-modified hollow mesoporous Prussian blue nanosystem co-delivering BAPTA-AM and gabexate mesylate not only suppressed TNF-α and IL-6 expression but also increased IL-10 levels and shifted macrophages from an M1- to an M2-like phenotype, indicating the activation of compensatory immunoregulatory pathways [ 51 ] (Fig. 10 ). Fig. 10 Fabrication process of biomimetic HMPB NPs and their therapeutic mechanism in a mouse model of AP induced by sodium taurocholate retrograde infusion (Reproduced from Wang et al. [ 51 ]. © American Chemical Society. Published with permission) Fabrication process of biomimetic HMPB NPs and their therapeutic mechanism in a mouse model of AP induced by sodium taurocholate retrograde infusion (Reproduced from Wang et al. [ 51 ]. © American Chemical Society. Published with permission) Collectively, these examples illustrate that nanotherapy can attenuate the inflammatory cascade at several levels, from targeted delivery of anti-inflammatory drugs and biomimetic cytokine trapping to active reprogramming or depletion of proinflammatory immune cells. This multilayered control of inflammation underpins many of the beneficial effects observed in preclinical AP models [ 22 , 25 , 32 , 40 , 51 , 65 – 67 ]. Excessive production of ROS in the pancreas and distant organs contributes to membrane damage, activation of inflammatory signaling, and cell death. Therefore, strengthening antioxidant defenses is a key therapeutic objective. Nanomaterials are particularly attractive in this context because they can (i) directly scavenge ROS as enzyme-mimetic “nanozymes,” (ii) deliver antioxidant compounds with improved pharmacokinetics, and (iii) activate endogenous antioxidant pathways such as Nrf2/HO-1. Typical readouts of these effects include reduced malondialdehyde (MDA) and nitric oxide levels; restoration of glutathione redox balance; and increased activity of SOD, catalase, and glutathione peroxidase, often accompanied by Nrf2 pathway activation. Selenium nanoparticles exemplify direct radical-scavenging nanodrugs. Nano-Se reduces pancreatic MDA and NO levels while increasing total antioxidant capacity and improving histological appearance in experimental AP [ 23 ]. Yttrium oxide nanoparticles display similarly potent radical-scavenging activity, lowering superoxide and other ROS, restoring GSH, SOD, and catalase levels, and activating Nrf2-dependent antioxidant responses (including increased NQO1 expression) in the pancreas [ 33 ]. Co-administration of CeO 2 and Y 2 O 3 nanoparticles has been shown to further ameliorate oxidative stress–induced pancreatic injury by normalizing catalase activity, limiting apoptosis in the islets of Langerhans, and improving insulin and ADP/ATP ratios [ 64 ]. Cinnamic acid–loaded nanoparticles combine delivery of an antioxidant phytochemical with inhibition of stress-responsive signaling (ASK1/JNK/p38, NLRP3, and NF-κB), thereby reducing serum amylase and lipase, lowering pancreatic MDA content, and alleviating tissue injury in AP models [ 29 ]. Other nanoplatforms use natural antioxidant molecules but optimize their delivery and release profiles. Bilirubin nanoparticles targeting the inflamed pancreas substantially reduce tissue ROS and MDA levels, increase SOD activity, and activate the Nrf2/HO-1 axis, highlighting simultaneous pharmacological and genomic antioxidant responses [ 26 ]. FA@zein-CS nanoparticles based on ferulic acid and chondroitin sulfate leverage CD44-mediated targeting and stimuli-responsive release (pH, GSH, and ROS) to concentrate antioxidant activity in damaged pancreatic tissue while maintaining excellent biocompatibility [ 59 ] (Fig. 11 ). Fig. 11 Illustration of FA@zein-CS in the treatment of acute pancreatitis (Reproduced from Lu et al. [ 59 ]. © Oxford University Press. Distributed under the Creative Commons CC-BY-NC-ND license) Illustration of FA@zein-CS in the treatment of acute pancreatitis (Reproduced from Lu et al. [ 59 ]. © Oxford University Press. Distributed under the Creative Commons CC-BY-NC-ND license) Multiple inorganic nanozyme systems provide broad ROS detoxification by mimicking endogenous antioxidant enzymes. Biodegradable molybdenum diselenide (MoSe 2 ) nanoparticles and ultrasmall iridium nanoparticles stabilized with polyvinylpyrrolidone catalyze the decomposition of hydrogen peroxide, dismutation of superoxide, and removal of hydroxyl radicals, leading to marked reductions in pancreatic H 2 O 2 , ·OH, O 2 ·− , and MDA accumulation in AP models [ 37 , 44 ]. Particular emphasis has been placed on targeting mitochondrial ROS (mtROS), which is a major source of oxidative damage in stressed PACs. Tungstate-based nanocomposites (mTWNDs), modified with melanin and tannic acid, bind mitochondrial outer membrane proteins such as TOM20 and type III collagen in damaged tissues, allowing selective mtROS scavenging, ΔΨm restoration, and protection from mitochondrial oxidative injury [ 52 ]. Overall, the antioxidant arm of nanotherapy acts at both the cytoplasmic and mitochondrial levels and frequently intersects with its anti-inflammatory effects, as reductions in ROS directly translate into decreased activation of redox-sensitive inflammatory pathways. Mitochondria are central regulators of PAC survival. In AP, mitochondrial dysfunction is characterized by the loss of ΔΨm, opening of the mitochondrial permeability transition pore (mPTP), swelling and structural disruption of mitochondria, cytochrome c release, and excessive production of mitochondrial ROS (mtROS). These events lead to ATP depletion and the activation of cell death pathways. Because mitochondrial injury occurs early and amplifies downstream damage, the restoration of mitochondrial function has become a key therapeutic objective, and many nanodrugs are now explicitly designed to accumulate in and protect mitochondria. Mitochondrial targeting can be achieved through several complementary design principles. Nanocarriers can be functionalized with ligands for mitochondrial membrane proteins or lipophilic cations, or equipped with ROS-sensitive linkers (such as thioketal groups) that trigger drug release in oxidizing microenvironments. Other platforms exploit biomimetic strategies, including the delivery of intact functional mitochondria or the enhancement of mitophagy to eliminate damaged organelles. Across these approaches, the shared goals are to preserve ΔΨm, prevent mPTP opening and cytochrome c release, limit mtROS generation, and maintain ATP synthesis. A representative example is the “three-stage amplifier” system developed by Yan et al. for severe AP [ 28 ]. This nanoplatform combines an M2-macrophage membrane coating, which promotes adhesion to inflamed endothelium, an octreotide ligand that directs the carrier to PACs via the somatostatin receptor SSTR-2, and an ROS-responsive polymer that enables drug release under oxidative stress [ 28 ]. In experimental SAP, this construct selectively accumulates in inflamed pancreatic tissue, prevents mPTP opening, preserves ΔΨm, reduces cytosolic cytochrome c, and attenuates mtROS production, collectively maintaining ATP generation and suppressing mitochondrial apoptotic pathways [ 28 ]. Direct delivery of mitochondria-targeted antioxidants is another effective strategy. Kaempferol-loaded thioketal-modified liposomes (DTM@KA) selectively concentrate in PAC mitochondria and release their cargo in response to ROS [ 38 ]. Kaempferol activates the TOM20–STAT6–Drp1/PINK1–Parkin axis, promoting mitophagy and clearance of damaged mitochondria (Fig. 12 ) [ 38 ]. Treatment with DTM@KA restored the GSH/GSSG ratio and activated Nrf2/HO-1 signaling, indicating an improved mitochondrial redox status and function [ 38 ]. Fig. 12 Schematic of the study of DTM@KA NP preparation and protective function as well as the possible mechanism by which mitochondrial function and oxidative stress are regulated by TOM20-STAT6-Drp1-mitophagy signaling in experimental SAPs (Reproduced from Wen et al. [ 38 ]. © Springer Nature. Distributed under the terms of the Creative Commons Attribution License, CC BY 4.0) Schematic of the study of DTM@KA NP preparation and protective function as well as the possible mechanism by which mitochondrial function and oxidative stress are regulated by TOM20-STAT6-Drp1-mitophagy signaling in experimental SAPs (Reproduced from Wen et al. [ 38 ]. © Springer Nature. Distributed under the terms of the Creative Commons Attribution License, CC BY 4.0) An even more radical strategy involves the biomimetic delivery of intact mitochondria. Zhang et al. generated “immunomitochondria” (nMITO) by cloaking functional mitochondria with neutrophil-derived membranes [ 49 ]. These nanomaterials retain adhesion molecules that mediate binding to damaged endothelium and are transferred to recipient cells via tunneling nanotubes [ 49 ]. In systemic inflammation models mimicking severe AP, nMITO therapy restored ΔΨm, normalized ATP levels, reduced mtROS, and prevented mPTP opening in pancreatic, hepatic, and cardiac tissues, resulting in broad multi-organ functional recovery [ 49 ]. Several conventional nanoantioxidants have also exhibited mitochondrial activity. Ultrasmall iridium nanoparticles improve the ultrastructure of PAC mitochondria and enhance the activity of respiratory chain complexes I and IV, in addition to their multienzyme-mimetic antioxidant action [ 44 ]. The tungsten-based nanoantioxidant mTWND targets the TOM20 protein on the mitochondrial outer membrane, providing highly localized neutralization of reactive species and protection against oxidative lipid peroxidation of mitochondrial membranes [ 52 ]. Collectively, mitochondria-targeted nanodrugs act at a fundamental level of cellular homeostasis, restoring bioenergetic capacity, stabilizing mitochondrial integrity, and preventing mitochondria-dependent cell death in AP. Immune dysregulation is a hallmark of AP, with excessive activation of neutrophils, monocytes/macrophages, and T lymphocytes driving local pancreatic injury and systemic complications. Nanotherapeutics can modulate these responses at several levels by reprogramming or depleting specific immune cell subsets, attenuating inflammasome and pattern-recognition receptor signaling, and amplifying endogenous regulatory pathways such as IL-10, IDO, and PD-L1. The first group of nanodrugs primarily targets the macrophages. Mannosylated chitosan–lipid nanocapsules loaded with emodin (M-CS-E-LNC) are taken up by macrophages via mannose receptors, rebalancing lipid metabolism and skewing polarization away from the proinflammatory M1 phenotype [ 32 ]. Selenized polysaccharide nanoparticles cloaked with macrophage membranes (mSe-PP) reduce TNF-α, IL-6, and MCP-1 levels, inhibit AKT/mTOR signaling, and restore autophagic flux, thereby limiting macrophage-driven inflammation [ 46 ]. Similarly, the biomimetic nanoenzyme MPBZC, composed of a Prussian blue core within a ZIF-8 shell coated with a macrophage membrane, combines ROS scavenging with the promotion of mitophagy and the upregulation of CD163, favoring an anti-inflammatory macrophage phenotype [ 47 ]. Other platforms can be used to manipulate the number or activity of overactivated leukocytes. Liposomal clodronate selectively depletes infiltrating macrophages and monocytes, attenuates the release of proinflammatory cytokines, and alleviates tissue injury in severe AP [ 63 ]. Hybrid platelet–apoptotic cell membrane–coated nanoparticles (PC@PLGA) decorated with calreticulin bind to activated neutrophils and promote their clearance by macrophages, resulting in a marked reduction in neutrophil infiltration in pancreatic and pulmonary tissues and lower circulating TNF-α, IL-6, and IL-1β levels [ 54 ]. Nanotechnology has also been used to potentiate the immunosuppressive properties of mesenchymal stem cells (MSCs). Aloe-emodin–loaded nanoparticles increase MSC expression of IDO and PD-L1, strengthening their capacity to dampen systemic TNF-α and restrain inflammatory responses [ 60 ]. A combinatorial nanoplatform that delivers chloroquine and tamoxifen to MSCs activates the IFN-γ–Akt–iNOS/IDO signaling axis, further augmenting MSC-mediated immune regulation [ 45 ]. In addition to cellular targeting, several nanosystems act directly on intracellular inflammatory sensors. Tuftsin-modified nanoparticles inhibit P2X7–NLRP3 inflammasome signaling, curbing IL-1β release and mitigating both local and systemic inflammation [ 30 ] (Fig. 13 ). Nanoliposomes containing curcumin or caffeic acid phenethyl ester (CAPE) suppress NF-κB nuclear translocation in macrophages and neutrophils, thereby reducing the transcription of multiple proinflammatory mediators [ 65 , 66 ]. Fig. 13 Synthesis of DSSM@TN NPs and its therapeutic impact (Reproduced from Wen et al. [ 30 ]. © American Chemical Society. Published with permission) Synthesis of DSSM@TN NPs and its therapeutic impact (Reproduced from Wen et al. [ 30 ]. © American Chemical Society. Published with permission) Overall, nanotherapeutics exert broad immunomodulatory effects in AP by dampening pathological immune hyperactivation (excessive neutrophil activity, macrophage-driven inflammation, and inflammasome signaling) while enhancing anti-inflammatory and regulatory circuits (M2 polarization, IL-10, IDO, and PD-L1). This dual action attenuates tissue damage in the acute phase and facilitates the resolution of inflammation and the restoration of immune homeostasis. Cytoprotection refers to the ability of therapeutic agents to protect cells from injury and to increase their survival. In AP, PACs are the primary cellular targets of damage, and severe disease also endangers distant organs, such as the liver, lungs, and kidneys. Massive PAC death through necrosis, apoptosis, and other forms of regulated cell death exacerbates disease progression by releasing digestive enzymes, amplifying tissue destruction, and fueling systemic inflammatory responses. Consequently, the direct protection of PACs and vulnerable extra-pancreatic cells is a critical goal of nanotherapy in AP. Many nanodrugs confer cytoprotection indirectly by attenuating inflammation and oxidative stress; however, several platforms have also demonstrated direct protective effects. Bilirubin nanoparticles, designed for targeted pancreatic delivery and enzyme-responsive release, not only reduced ROS and MDA levels and activated Nrf2/HO-1 signaling but also diminished PAC necrosis and improved cell viability in murine AP [ 26 ]. Histology confirmed smaller necrotic areas, consistent with direct parenchymal protection [ 26 ]. Another strategy addresses the toxic intracellular Ca 2+ overload, which is a central driver of premature zymogen activation and PAC injury. Liposomal nanoparticles loaded with the intracellular calcium chelator BAPTA-AM penetrate PACs, normalize cytosolic Ca 2+ levels, and prevent calcium-induced cytotoxicity [ 43 ]. In vivo, BAPTA-liposomes reduced the number of TUNEL-positive cells, downregulated necrosis markers, and markedly decreased the autoactivation of pancreatic enzymes, effectively shielding PACs from self-digestion [ 43 ] (Fig. 14 ). Fig. 14 Schematic illustration of the proposed mechanism by which BLN protects pancreatic cells in a rat model of AP through preventing intracellular calcium overload. AP, acute pancreatitis; BLN, BAPTA-AM-loaded liposome nanoparticles; BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N, N,N’,N’-tetraacetic acid tetrakis (acetoxymethyl ester); p, phosphorylated; TC, sodium taurocholate; ROS, reactive oxygen species; MLKL, mixed lineage kinase domain-like protein; RIP, receptor interaction protein; FADD, fas-associating protein with death domain (Reproduced from Fu et al. [ 43 ]. © Spandidos Publications. Distributed under the Creative Commons CC-BY-NC-ND license) Schematic illustration of the proposed mechanism by which BLN protects pancreatic cells in a rat model of AP through preventing intracellular calcium overload. AP, acute pancreatitis; BLN, BAPTA-AM-loaded liposome nanoparticles; BAPTA-AM, 1,2-bis(2-aminophenoxy)ethane-N, N,N’,N’-tetraacetic acid tetrakis (acetoxymethyl ester); p, phosphorylated; TC, sodium taurocholate; ROS, reactive oxygen species; MLKL, mixed lineage kinase domain-like protein; RIP, receptor interaction protein; FADD, fas-associating protein with death domain (Reproduced from Fu et al. [ 43 ]. © Spandidos Publications. Distributed under the Creative Commons CC-BY-NC-ND license) Nanotherapeutics can also preserve cell viability in highly inflamed environments. Macrophage membrane–coated nanoparticles carrying ulinastatin protected human pancreatic duct epithelial cells (HPDE6-C7) in an in vitro pancreatitis model, suggesting that the nanocarrier provides sustained protection against proteolytic injury in addition to targeted drug delivery [ 41 ]. A dual-targeting nanosystem that combines a neutrophil membrane coating with a PAC-specific ligand exemplifies integrated cytoprotection, which decreases pancreatic necrotic areas, preserves cellular ATP content and enzymatic activity, and suppresses intrapancreatic trypsin activity in vivo [ 51 ]. Thus, the nanodrug simultaneously buffers against inflammatory damage, blocks autodigestive enzyme activation, and maintains acinar cell metabolic competence [ 51 ]. Importantly, nanotherapeutics can mitigate secondary organ injury associated with AP. Neutrophil-clearing nanoparticles (PC@PLGA) markedly attenuate pulmonary damage, edema, hemorrhage, and neutrophil infiltration in alveolar spaces, and improve oxygenation indices [ 54 ]. Mitochondria-delivering systems such as nMITO, as discussed above, extend cytoprotection to cardiac and hepatic tissues in models of AP-induced multi-organ failure, restoring organ function alongside pancreatic recovery [ 49 ]. These findings underscore the multifaceted cytoprotective role of nanotherapy, not only in limiting local pancreatic injury but also in supporting cellular resilience and tissue regeneration across multiple organs. A hallmark of AP is the pathological activation of pancreatic enzymes, such as trypsin, phospholipase A 2 , and elastase, within the gland, leading to autodigestion of pancreatic tissue. In severe forms of AP, non-canonical cell death pathways, including ferroptosis (induced by iron-dependent lipid peroxidation) and PANoptosis (a programmed necro-apoptotic process combining apoptosis, necroptosis, and pyroptosis), are also activated. Modern nanosystems provide targeted strategies for modulating these key pathological mechanisms through anti-enzymatic and other specific therapeutic effects. The anti-enzymatic action of nanodrugs involves the direct inhibition or neutralization of active pancreatic enzymes, aiming to halt the self-destructive process within the organ. Nanomaterials can be loaded with protease inhibitors or can act as enzyme traps. In parallel, anti-PANoptosis and anti-ferroptosis effects are designed to prevent widespread cell death by targeting specific intracellular pathways, such as inhibiting necroptosis mediators (e.g., RIPK3) and pyroptosis mediators (e.g., caspase-1, caspase-11, and gasdermins), or by reducing iron-dependent free radical generation and lipid peroxidation associated with ferroptosis. In a study by Zhang et al., a representative anti-enzymatic approach was demonstrated through the development of biomimetic nanoparticles coated with macrophage membranes that incorporated a “lure-and-neutralize” mechanism against phospholipase A 2 [ 39 ] (Fig. 15 ). These MO-NP(L&K) particles display melittin peptides on their surface, which act as bait for phospholipase A 2 , which is subsequently neutralized by the incorporated MJ-33 inhibitor [ 39 ]. This strategy significantly reduces the activity of free phospholipase A 2 in the pancreas, limiting membrane injury and lysolipid formation, which are key contributors to autodigestion. Notably, this “antiphospholipase” nanotherapy also exhibited systemic anti-inflammatory effects; mice treated with these particles showed markedly reduced levels of IL-6, TNF-α, and IL-1β, along with suppressed NF-κB activation in tissues [ 39 ]. These findings underscore how the selective targeting of a single enzyme can favorably alter disease outcomes in AP. Fig. 15 Schematic representation of MΦ-NP(L&K) designed to inhibit PLA 2 during AP progression (Reproduced from Zhang et al. [ 39 ]. © Springer Nature. Distributed under the terms of the Creative Commons Attribution License, CC BY 4.0) Schematic representation of MΦ-NP(L&K) designed to inhibit PLA 2 during AP progression (Reproduced from Zhang et al. [ 39 ]. © Springer Nature. Distributed under the terms of the Creative Commons Attribution License, CC BY 4.0) Another key enzyme, trypsin, which is the initiator of zymogen activation, has also been targeted by nanotherapeutic strategies. Dual-targeting nanoparticles engineered to home both to the inflamed endothelium and to PACs effectively deliver a small-molecule trypsin inhibitor directly to the pancreas [ 51 ]. Trypsin activity in pancreatic tissue was significantly reduced, and the extent of PAC necrosis was markedly lower than in untreated controls [ 51 ]. The anti-enzymatic effects of nanotherapy can also be achieved indirectly by restoring ionic homeostasis, particularly that of Ca 2+ , since calcium overload and ATP depletion are major drivers of uncontrolled enzyme activation. The administration of BAPTA-loaded nanoliposomes successfully eliminated intracellular Ca 2+ triggers, thereby preventing enzyme activation and protecting PACs from autodigestion [ 43 ]. Even with effective enzyme inhibition and inflammation suppression, massive cell death, particularly in immune cells, can perpetuate the disease process. Therefore, the inhibition of necrotic pathways remains of significant therapeutic interest, and nanomedical approaches offer the ability to prevent excessive cell death. One example is a trypsin-sensitive biomimetic nanosystem based on mesoporous organosilicate (SL@M@Arg-MSN@BA) that encapsulates the Ca 2+ chelator BAPTA-AM [ 50 ]. This system ensures targeted delivery to injured PACs and on-demand drug release in the presence of trypsin. In vivo, it efficiently reduced intracellular calcium overload, restored the redox balance, blocked inflammatory cascades, and suppressed cell necrosis. Specifically, it reduced intracellular Ca 2+ levels by 81.3%, decreased serum lipase and amylase levels by more than 60%, significantly improved pancreatic function, and increased survival in AP-induced mice from 50% to 91.6% [ 50 ]. Wu et al. used nanoparticles coated with macrophage membranes and loaded them with a polyphenolic compound that selectively accumulated in inflamed pancreatic tissues and resident macrophages [ 34 ]. This nanotherapeutic inhibited PANoptosis: in pancreatic macrophages from treated animals, the expression of key PANoptosis-related proteins (ZBP1, RIPK3, and caspase-6) was markedly reduced, and the proportion of apoptotic/necrotic (TUNEL⁺) macrophages was significantly lower [ 34 ]. This strategy effectively prevents macrophage depletion and mitigates excessive cytokine release owing to necrotic death, thereby attenuating systemic inflammation. Another non-canonical cell death mechanism, ferroptosis, is characterized by uncontrolled lipid peroxidation driven by iron-derived radicals. Under the oxidative stress conditions present in AP, ferroptosis can exacerbate PAC damage. A targeted anti-ferroptosis strategy was demonstrated by Li et al., who employed Ca/Fe-based nanoenzyme particles capable of degrading peroxides and superoxides, thus reducing the primary ferroptotic trigger, excess ROS [ 77 ]. In a murine model of TG-induced AP, this nanotherapeutic significantly reduced serum amylase and lipase activity, decreased proinflammatory cytokine levels (IL-1β, IL-6, and TNF-α), and attenuated neutrophil infiltration [ 77 ]. These findings indicate that antioxidant-mediated inhibition of ferroptosis contributes to the resolution of inflammation and the repair of pancreatic tissue. Additionally, some nanotherapeutics target pyroptosis, a form of inflammatory cell death mediated by gasdermins and inflammatory caspases. The multifunctional nanosystem described above not only restored mitochondrial function but also inhibited pyroptosis by blocking caspase-11 and gasdermin E in PACs [ 28 ]. This results in a reduced release of intracellular danger-associated signals and diminished immune cell recruitment, thereby curbing secondary inflammation [ 28 ]. Taken together, these studies demonstrate that nanotherapy can selectively modulate critical pathological processes in AP, from the neutralization of aggressive enzymes to the suppression of recently characterized cell death pathways, thereby offering robust cytoprotective and therapeutic effects. Recent findings strongly suggest that nanotherapeutics can comprehensively mitigate the course of acute pancreatitis by targeting its fundamental pathogenic mechanisms. Nanotherapy suppresses excessive inflammation, neutralizes oxidative stress, modulates immune responses, protects cells from death, and prevents enzymatic autodigestion. Many nanoparticles possess multifunctional capabilities, combining anti-inflammatory, antioxidant, and cytoprotective properties within a single platform [ 26 , 52 ]. Through targeted delivery mechanisms, such as cell membrane coatings, receptor ligands, or responses to physiological cues (e.g., pH or enzyme activity), these agents achieve high local concentrations in the pancreas while sparing healthy tissues. In preclinical models (mice and rats), such nanopreparations significantly reduced mortality, decreased pancreatic necrosis, prevented multi-organ failure, and accelerated recovery [ 34 , 51 , 54 ]. These outcomes highlight the considerable therapeutic potential of nanomedicine in the treatment of acute pancreatitis. The prospects for clinical translation appear promising: nanopreparations based on biocompatible materials, such as liposomes, polymers, and biomembranes, are likely to offer a favorable safety profile and superior efficacy compared with conventional formulations owing to enhanced targeting capabilities. Further studies are required to evaluate the long-term safety, pharmacokinetics, and scalability of nanodrug production. Accumulating evidence indicates that nanotherapy holds great promise for the treatment of acute pancreatitis. In the future, combining different nanotherapeutics or designing multifunctional nanoplatforms could enable the simultaneous modulation of all major pathogenic pathways, including inflammation, oxidative stress, enzymatic degradation, and cell death, ultimately transforming the management of this severe disease. Thus, nanomedicine may bridge a critical gap in pancreatitis therapy by offering a more precise, effective, and safe treatment strategy.