Baicalin-Loaded MOF-818 Nanozyme for Ischemic Stroke Treatment via ROS Scavenging and Neuroinflammation Suppression

Baicalin-Loaded MOF-818 Nanozyme for Ischemic Stroke Treatment via ROS Scavenging and Neuroinflammation Suppression | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 19 November 2025 V1 Latest version Share on Baicalin-Loaded MOF-818 Nanozyme for Ischemic Stroke Treatment via ROS Scavenging and Neuroinflammation Suppression Authors : Wei Shen , YuChen Wang , Xiaosong Zhu , Xiaojuan Chen , Xianjun Wang , and Fengyuan Che [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176355580.02628044/v1 169 views 93 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Background： Ischemic stroke (IS) reperfusion induces neuronal damage through excessive reactive oxygen species (ROS) and neuroinflammation. Baicalin (Bai) shows antioxidant and anti-inflammatory effects but suffers from poor solubility and bioavailability. MOF-818, a zirconium-based framework with superoxide dismutase- and catalase-mimicking activity, efficiently scavenges ROS but lacks pharmacological versatility. Combining Bai with MOF-818 may offer multitarget neuroprotection in IS. To investigate the therapeutic efficacy and mechanisms of Bai-loaded MOF-818 (Bai@MOF-818) in IS. Experiments： In vitro oxygen-glucose deprivation/reperfusion (OGD/R) models using PC-12 cells and BV-2 microglia were employed to assess ROS scavenging, mitochondrial protection, apoptosis, and microglial polarization. In vivo, Bai@MOF-818 was stereotactically delivered into the ischemic core of rats subjected to transient middle cerebral artery occlusion. Neurological function, infarct volume, oxidative stress, apoptosis, and microglial polarization were evaluated. Results： Bai@MOF-818 markedly scavenged ROS, restored mitochondrial membrane potential, and promoted M1-to-M2 microglial polarization via NF-κB inhibition and PPARγ activation. This led to reduced TNF-α/IL-6 and increased IL-10/Arg-1, alleviating neuroinflammation. Furthermore, Bai@MOF-818 inhibited neuronal apoptosis by suppressing Bax and cleaved caspase-3 while elevating the Bcl-2/Bax ratio. Histological analyses revealed preserved tissue integrity, enhanced neuronal survival, reduced infarct size and edema, and improved motor and sensory recovery. Conclusions： Bai@MOF-818 exerts synergistic antioxidant and anti-inflammatory actions, attenuates neuronal apoptosis, and enhances neurological recovery, representing a promising multitarget therapeutic for cerebral ischemia-reperfusion injury. Introduction Stroke, a cerebrovascular condition characterized by acute neurological dysfunction, is a serious global health threat due to its widespread incidence and high disability and mortality rates [1]. Ischemic stroke (IS), which accounts for approximately 87% of stroke events, is triggered by a significant reduction in cerebral blood supply due to embolic or thrombotic interference [2]. Although the rapid restoration of cerebral blood flow before thrombolytic window closure is widely regarded as the most effective intervention for IS [3], tissue plasminogen activator (tPA) is the only FDA-approved treatment for IS. However, its narrow 4.5 h window precludes the treatment of > 90% of patients [4, 5]. Endovascular thrombectomy (ET) has recently gained popularity in stroke therapy, but its limited 6-h treatment window and potential procedural risks remain major clinical challenges [6, 7]. Despite the partial recovery of cerebral perfusion through these measures, reperfusion immediately induces excessive production of ROS, notably superoxide anion (•O 2 ⁻) and hydrogen peroxide (H₂O₂) [8, 9]. Excessive ROS load induces the overexpression of cytokines and adhesion molecules, triggering a “cytokine storm” [10]. Combined oxidative and inflammatory stress dismantles tight junction proteins, compromises the blood–brain barrier, and significantly elevates vascular permeability, leading to diffuse edema and hemorrhagic conversion [11-13]. The resulting cascade accelerates widespread neuronal apoptosis, collapses the penumbra into the infarct core, and severely impairs functional recovery [14, 15]. Due to these therapeutic limitations, it is imperative to develop a novel treatment strategy that is both safe and capable of targeting multiple pathological processes, thereby improving neuroprotection in IS and reducing mortality and disability. Baicalin (Bai) is an important flavonoid compound extracted from the medicinal plant Scutellaria baicalensis Georgi. It exhibits numerous biological activities, including antioxidant, anti-inflammatory, and anti-apoptotic effects [16-18]. Bai exhibits significant neuroprotective effects by reducing neuroinflammation and inhibiting astrocyte reactivity in a transient middle cerebral artery occlusion model of C57BL/6J mice [19]. Moreover, Bai restores the neuronal PDK2-PDH axis function by inhibiting SDH-mediated oxidative damage, underscoring its potential as a therapeutic agent for acute IS [20]. Despite its promising application in stroke treatment, the development of Bai as a clinically viable therapeutic agent remains limited [21]. The poor lipid and water solubility of Bai results in the low bioavailability of its clinical preparations, necessitating higher dosages to reach therapeutic levels [22]. High doses of Bai can saturate its bioavailability, increase hepatic and renal metabolic burden, and suppress coagulation, thereby elevating liver enzymes, tubular injury, and increasing the risk of bleeding [23, 24]. Consequently, improving its delivery efficiency and bioavailability is imperative to reduce the required dose of Bai, thereby minimizing drug-related side effects and improving therapeutic efficacy. Nanozymes represent a category of nanomaterials possessing enzyme-mimetic activities, exhibiting superior characteristics compared to natural enzymes, including cost-effectiveness, accessibility, and enhanced stability, thereby serving as promising carriers for therapeutic applications [25]. Among the numerous nanozyme platforms currently available, metal-organic frameworks (MOFs) are viewed as promising biomimetic enzyme materials owing to their exceptional specific surface areas, controllable porous structures, tailorable chemical compositions, and versatile catalytic centers [26]. Due to their exceptional pharmaceutical loading capacity, biodegradable framework, and superior biocompatibility, MOFs are frequently used as functional carriers to achieve extended release profiles, thereby optimizing the delivery efficiency and alleviating drug toxicity [27-29]. Some MOFs not only serve as drug carriers but also possess intrinsic biological activities, including photosensitivity, enzyme-mimetic properties, and controlled metal ion release [27]. These inherent functions enable MOFs to actively generate oxygen, scavenge ROS, and catalyze Fenton-like reactions at pathological sites [30-32]. The combination of bioactivity of the carrier with the pharmacological effects of the encapsulated drug results in a phenomenon known as the “carrier–drug synergy” effect. This synergy refers to the process in which the carrier not only facilitates drug delivery but also exerts its biological effects, thereby collaborating with the drug to improve the overall therapeutic efficacy significantly [33-35]. For instance, ZIF-8 loaded with methyl vanillate promotes osteogenic differentiation of hBMSCs while exhibiting antimicrobial properties [36]. Superoxide dismutase (SOD) catalyzes the conversion of •O 2 − into H 2 O 2 and O 2 , while catalase (CAT) catalyzes the breakdown of H 2 O 2 into harmless water and O 2 [37]. Dong et al. discovered that by leveraging the potent SOD/CAT-like enzymatic activity of MOF-818, the antioxidative system (MOF/Gel) removes ROS and improves diabetic wound healing through anti-inflammatory therapeutic effects [38]. Based on these studies, we synthesized a novel drug delivery system, Bai@MOF-818, to address the limitations of Bai, including poor solubility, low bioavailability, and rapid metabolism. MOF-818 exhibits high porosity and excellent biocompatibility, enabling efficient drug loading and sustained release. Additionally, its intrinsic SOD/CAT-like activity enables effective ROS scavenging. Through a synergistic “carrier-drug” mechanism, Bai@MOF-818 simultaneously reduced oxidative stress and exerted anti-inflammatory and neuroprotective effects, thereby improving therapeutic outcomes in IS (As shown in Scheme 1). The efficacy of Bai@MOF-818 was confirmed through in vitro and in vivo experiments, indicating a promising strategy for stroke therapy. Scheme 1. Schematic illustration of Bai@MOF-818 therapy for ischemic stroke via ROS clearance, immune modulation, and anti-inflammatory effects. Materials and methods Synthesis of MOF-818 A modified single-step solvothermal approach was used to synthesize MOF-818 [39]. A mixture of Cu(NO 3 ) 2 ·3H 2 O (124 mg), ZrOCl 2 ·8H 2 O (42.5 mg), H 2 PyC (32.5 mg), and trifluoroacetic acid (120 μL) was prepared in 20 mL DMF using ultrasonication. The resulting solution was then placed in a 50 mL PTFE-lined autoclave and heated at 100 °C for 10 h. Blue crystals were harvested through centrifugation after cooling, washed with DMF and ethanol, and dried at 60 °C for 12 h. Drug loading ratio The loading efficiency of Bai in MOF-818 nanoparticles was determined using centrifugal analysis. Bai and MOF-818 were mixed at different weight ratios and centrifuged after incubation. The supernatant was analyzed using UV–vis spectroscopy (275 nm) to determine the amount of Bai. The loading and encapsulation efficiencies were calculated as follows: \(\text{Loading\ efficiency\ }\left(\%\right)=\frac{M_{\text{Bai}}-C_{1}V_{1}-C_{2}V_{2}}{M_{\text{FU}}}\times 100\) \(\text{\ Encapsulation\ efficiency\ }\left(\%\right)=\frac{M_{\text{Bai}}-C_{1}V_{1}-C_{2}V_{2}}{M_{\text{Bai}}}\times 100\) M Bai is the initial Bai input, and M MOF-818 is the initial MOF-818 input. C 1 and C 2 represent the concentrations of Bai in the first supernatant obtained after centrifugation and the second supernatant after washing with 5 mL of deionized water, respectively. V 1 and V 2 represent the volumes of the two supernatants. Drug release rate Bai@MOF-818 (5 mL in PBS) was dialyzed against 95 mL of PBS at the same pH for 24 h at room temperature and in the dark. At each time point, 5 mL dialysate was withdrawn and replaced with fresh buffer. Absorbance at 275 nm was measured to determine Bai concentration using the standard curve. The cumulative release rate was calculated as follows: \begin{equation} C\text{umulative\ drug\ }\text{release}\left(\%\right)=\frac{V_{e}\sum_{1}^{n-1}C_{i}+C_{n}V_{0}}{M}\times 100\nonumber \\ \end{equation} Herein, V e represents the volume of each sample, V 0 is the total volume of the dialysate, C i is the concentration of Bai in the sample collected at the i time point, M is the dosage of Bai, and n is the number of sampling times. SOD-like activity of MOF-818 Under alkaline conditions, pyrogallol undergoes autoxidation to quinone, generating superoxide radicals (•O 2 ⁻) with an absorption peak at 325 nm. A solution of 4.5 mL Tris-HCl buffer (0.1 M, pH 8.20, with 2.0 mM EDTA) and 4.2 mL deionized water was equilibrated at 25 °C for 20 min. Subsequently, 0.3 mL of 2.5 mM pyrogallol (or 0.01 mmol/L HCl for the control) was added, mixed rapidly, and the absorbance at 325 nm was monitored continuously for 20 min. The •O 2 ⁻ scavenging rate was calculated using the following equation: Inhibition rate = (ΔA₀ − ΔA₁)/ΔA₀ × 100% where ΔA₀ and ΔA₁ represent absorbance changes without and with MOF-818, respectively. CAT-like activity of MOF-818 To assess the CAT-like activity, the decomposition of 20 mM H₂O₂ was monitored in real time by recording the dissolved oxygen concentration over 10 min using a dissolved oxygen meter. Cellular uptake assay Rhodamine B-labelled Bai@MOF-818 was incubated with PC-12 cells at various time points (6, 12, and 24 h). Following fixation and nuclear staining (Hoechst 33342), the intracellular distribution was visualized using confocal microscopy. Cell culture and induction of the oxygen-glucose deprivation/reoxygenation (OGD/R) injury model Mouse microglial BV-2 cells (BV-2) and rat pheochromocytoma PC-12 cells (PC-12) were cultured in Dulbecco’s modified Eagle medium (DMEM) containing 10% fetal bovine serum and 1% penicillin/streptomycin at 37 °C under 5% CO 2 conditions. Following 24 h of standard culture, the cells were washed thrice with phosphate-buffered saline (PBS), transferred to glucose-free DMEM, and incubated in a hypoxic environment of 5% CO 2 and 95% N 2 for 2 h to induce OGD. After hypoxia, the medium was replaced with complete DMEM, and the cells were incubated under normal conditions (37 °C and 5% CO 2 ) for 24 h to simulate the reoxygenation phase. Cell viability assay and cytotoxicity evaluation The cytocompatibility of Bai@MOF-818 was evaluated using live/dead cell staining (Invitrogen, Waltham, MA, USA) and Cell Counting Kit-8 (CCK-8) assay (Beyotime, Shanghai, China). For live/dead staining, PC12 cells were incubated with Bai@MOF-818 at specific concentrations for 24 h. The cells were stained according to the manufacturer’s protocol. Fluorescence images were captured using a confocal laser-scanning microscope. For cytotoxicity assessment, PC12 cells were co-incubated with different concentrations of Bai@MOF-818 or various treatment groups for 1 d. Subsequently, 10 μL of CCK-8 solution was added to each well and incubated for 2 h, and the absorbance was measured at 450 nm. Measurement of intracellular ROS after OGD/R Intracellular ROS levels were determined using a ROS assay kit with DCFH-DA as the fluorescent probe. DCFH-DA enters cells and is hydrolyzed by intracellular esterases to non-fluorescent DCFH, which is then oxidized by ROS to generate fluorescent DCF. The fluorescence intensity of DCF indicates intracellular ROS levels. PC-12 Cells were seeded in 6-well plates and incubated for 24 h for adherence. The cells were then rinsed thrice with PBS and incubated with 10 μM DCFH-DA diluted in DMEM for 20 min at 37 °C in the dark. The ROS-associated DCF fluorescence was observed using a confocal microscope with excitation at 488 nm and emission at 525 nm. Western blotting Proteins were extracted using RIPA lysis buffer (Beyotime, China) containing protease and phosphatase inhibitors (Sigma–Aldrich, USA) to ensure protein stability. The lysates were collected by centrifugation, and protein concentrations were determined using the bicinchoninic acid assay. Equal amounts of protein were separated using sodium dodecyl sulfate polyacrylamide gel electrophoresis and transferred to 0.45 μm PVDF membranes (Millipore, USA). The membranes were blocked using 5% non-fat milk for 1 h at room temperature and incubated with specific primary antibodies overnight at 4 °C (Table S1), followed by incubation with HRP-conjugated secondary antibodies for 2 h at room temperature. Protein bands were visualized using enhanced chemiluminescence and quantified using the ImageJ software. Immunofluorescence staining Cells or tissue sections were fixed in 4% paraformaldehyde at room temperature to maintain structural integrity, followed by permeabilization with 0.3% Triton X-100 (Beyotime, China) for 10 min. Non-specific binding was blocked by incubating the samples with 5% goat serum (Beyotime, China) for 2 h. The samples were then incubated overnight at 4 °C with primary antibodies (Table S1). After washing with PBS, fluorescence-conjugated secondary antibodies were applied for 2 h at room temperature. DAPI staining was performed for 5 min. Fluorescence images were obtained using a fluorescence microscope. Gene expression Total RNA was extracted using an RNA Extraction Kit (Omega, USA). cDNA was synthesized using the PrimeScript RT reagent kit (Takara, Japan), and quantitative PCR was performed using SYBR Green master mix (Yeasen, China). GAPDH served as the internal control, and the relative gene expression levels were determined using the 2 –ΔΔCT method. The primers were obtained from Tsingke Biotech (China), and their sequences are listed in Table S2. TUNEL staining To assess apoptosis, TUNEL staining was performed on treated cells or sections using a commercial kit (Beyotime, China) with DAPI counterstaining for nuclei or additional neuronal labeling. Apoptotic cells were visualized under a fluorescence microscope as TUNEL-positive cells, and the apoptotic cell ratio was calculated. DHE staining To assess ROS levels in the brain tissue, dihydroethidium (DHE) fluorescent staining was performed according to the manufacturer’s instructions (Yeasen, China). After staining, the nuclei were labelled with DAPI. Red fluorescence from oxidized DHE was observed using a fluorescence microscope and quantified using ImageJ software. MCAO modeling All animal procedures were approved by the Ethics Committee of the Science and Technology Department of Linyi People’s Hospital (approval no. 202409-A-007). Male Sprague-Dawley (SD) rats weighing 220–250 g were used in this study. Animals were housed under controlled conditions with a 12-h light/dark cycle, temperature maintained at 20–26 °C, and relative humidity of 40%–70%. Food and water were provided ad libitum. To simulate IS, the middle cerebral artery occlusion/reperfusion (MCAO/R) model was established using the previously described suture-occlusion technique [40]. The rats were anesthetized using a small animal gas anesthesia apparatus and maintained under continuous anesthesia with 2% isoflurane. A silicone-coated monofilament was gently advanced through the external carotid artery (ECA) into the internal carotid artery to occlude the origin of the middle cerebral artery for 90 min. Following the occlusion period, the filament was carefully withdrawn to allow reperfusion. In the sham group, the distal ECA was ligated without filament insertion. The MCAO model rats were randomly divided into five groups: Sham, MCAO/R, Bai, MOF-811, and Bai @MOF-818. TTC staining and edema evaluation After 24 h of Middle cerebral artery occlusion (MCAO) operation, the brain tissues were collected and sectioned into 2 mm-thick slices. The sections were then incubated in a 2% 2,3,5-Triphenyltetrazolium chloride (TTC) solution at room temperature for 15 min. The stained brain slices were photographed and analyzed using ImageJ software. Brain tissues from another group of rats were collected to assess the brain water content. The wet weight was measured, followed by dehydration in an oven at 180 °C for 12 h to obtain the dry weight. The brain water content was then calculated based on the difference between wet and dry weights. Hematoxylin and eosin staining Paraffin-embedded brain sections were baked at 60 °C for 1 h, dewaxed with xylene, and rehydrated using graded ethanol. Hematoxylin staining was performed, and the cells were differentiated using 10% hydrochloric acid. Pathological changes in the brain tissue from MCAO rats were observed using a light microscope. Nissl staining After heating at 60 °C for 20 min, the paraffin sections were dewaxed in xylene, rehydrated with graded ethanol, and stained with Nissl solution at 58 °C for 40 min. After ethanol dehydration and xylene clearing, the sections were examined and photographed under a microscope. Neurological behavioral tests Neurological function after cerebral ischemia was assessed using the cylinder test, Longa score, and adhesive removal test. Forelimb asymmetry was assessed using the cylinder test, while the Longa scale (0–4) was used to measure neurological deficits, and the adhesive removal test was used to assess sensorimotor coordination by recording the time to remove adhesive tapes (0.3 × 0.4 cm) from the forepaws. All tests were performed 24 h postoperatively by blinded investigators. Statistical analysis Data are presented as mean ± standard deviation. One-way analysis of variance was performed to determine statistically significant differences (* p < 0.05, ** p < 0.01). Synthesis and characterization of Bai@MOF-818 MOF-818 was prepared using a modified solvothermal approach as previously described [39]. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images revealed that the synthesized MOF-818 exhibited a well-defined octahedral crystalline morphology with an average particle size of approximately 238 nm (Figures 1A and S1). The X-ray diffraction (XRD) pattern (Figure 1C) revealed characteristic peaks that were highly consistent with previously reported data [41, 42], indicating the excellent crystallinity of the material. Additionally, the nitrogen adsorption–desorption isotherm exhibited a typical type IV curve and a prominent hysteresis loop, confirming the presence of an ideal mesoporous framework with a pore size centered at 2.66 nm (Figure 1D). The large BET surface area of 1268 m 2 /g provides extensive adsorption surfaces and diffusion pathways, which are favorable for drug encapsulation and sustained delivery (Figure 1E). The X-ray photoelectron spectroscopy (XPS) survey spectrum revealed the presence of key elements, including C, O, N, Zr, and Cu (Figure 1F). High-resolution Cu 2p spectra revealed binding energies at 934.9 and 954.7 eV for Cu 2p₃/₂ and Cu 2p₁/₂, respectively, along with distinct satellite peaks, indicating the stable existence of Cu 2+ . Additionally, a single peak at 915 eV in the Cu LMM Auger spectrum confirmed the presence of Cu⁺ rather than Cu 0 . The coexistence of Cu⁺ and Cu 2+ provides a chemical basis for enzyme-mimetic catalytic activity. For drug delivery evaluation, a quantitative detection method was established for baicalin using UV-Vis analysis, indicating good linearity with high detection accuracy (Figures 1I-J). The loading capacity and encapsulation ratio of Bai@MOF-818 increased significantly up to a feeding ratio of 8, after which no further increase was detected (Figures S2 and 3). In vitro release experiments demonstrated that Bai@MOF-818 achieved a cumulative release rate of 71.4% within 24 h at pH 5.6, which was significantly higher than that of 31.2% at pH 7.4, indicating excellent acid-responsive controlled-release characteristics (Figure 1K). MOF-818 with high crystallinity and a large surface area was successfully synthesized, enabling efficient Bai loading and pH-sensitive release, making it a promising platform for targeted drug delivery in ischemic or inflammatory pathological microenvironments. Fig. 1. Synthesis and Characterization of Bai@MOF-818. (A) SEM and TEM images of MOF-818. (B) HAADF-STEM and EDS elemental mapping of MOF-818. (C) XRD patterns of MOF-818. (D) Pore distribution of MOF-818. (E) N 2 adsorption–desorption isotherms of MOF-818. (F) XPS survey scan of MOF-818. (G) Cu 2p XPS spectrum of MOF-818. (H) Cu LMM Auger electron spectra of MOF-818. (I) UV–visible absorbance of Bai. (J) Standard curve of Bai. (K) Release profiles of Bai@MOF-818 at pH 7.4 and 5.6. Evaluation of SOD- and CAT-like activities of MOF-818 Figure 2A depicts that MOF-818 first exhibited SOD-like catalysis to convert harmful superoxide radicals (O 2 ⁻) into hydrogen peroxide and oxygen, followed by CAT-like activity to catalyze the decomposition of hydrogen peroxide into water and oxygen. The antioxidant activity of MOF-818 was systematically assessed using the pyrogallol autoxidation system. A dose-dependent enhancement of the inhibitory effect was observed with increasing concentrations (Figures 2B-C). The ROS-scavenging efficiency of MOF-818 was significantly higher than that of conventional nanozymes, including MnO 2 , V 2 O 3 , CuO, and CeO 2 (Figure 2D). Additionally, MOF-818 demonstrated excellent CAT-like activity by accelerating H 2 O 2 decomposition and elevating dissolved oxygen levels in a concentration-dependent manner (Figures 2E-F), surpassing all control groups (Figure 2G). These results confirmed that MOF-818 possesses potent SOD- and CAT-like catalytic properties and represents a highly promising ROS-scavenging nanozyme platform. Fig. 2. ROS scavenging ability of MOF-818. (A) Schematic illustration of the SOD- and CAT-like activities of MOF-818. (B) Time-dependent absorbance changes of A-A 0 (325 nm) with different concentrations of MOF-818. (C) •O 2 − inhibition rates of Zn-MOF at different concentrations. (D) •O 2 − inhibition rates of different compounds (E) Kinetic curves of O 2 generation from H 2 O 2 decomposition catalyzed by MOF-818 at different concentrations. (F) Net oxygen generation from H 2 O 2 decomposition catalyzed by MOF-818. (G) CAT-mimetic performance of MOF-818 and other samples. Cytotoxicity and intracellular antioxidative activity of Bai@MOF-818 To evaluate cellular uptake efficiency, PC-12 cells were treated with Rhodamine B-labelled Bai@MOF-818. A time-dependent increase in red fluorescence was observed from 6 to 24 h, indicating efficient internalization and sustained intracellular accumulation (Figure S4). The CCK-8 assay revealed that Bai@MOF-818 exhibited negligible cytotoxicity at concentrations below 100 μg/mL without significant impact on cell viability. However, when the concentration reached or exceeded 150 μg/mL, cell viability decreased significantly, indicating potential cytotoxic effects at higher doses (Figure S5). In the OGD/R model, treatment with 50 and 100 μg/mL Bai@MOF-818 significantly improved cell survival, with the 100 μg/mL group demonstrating the strongest protective effect (Figure S6). After 24 h of culture, live/dead staining and CCK-8 viability assays were performed to systematically evaluate the cytotoxicity in each group (Figures 3A-B). The results revealed no significant differences in cell viability between the experimental and control groups, confirming the excellent biocompatibility of Bai@MOF-818. In the OGD/R injury model, DCFH-DA fluorescent probe detection revealed a significant elevation in intracellular ROS levels in the OGD/R group, while Bai, MOF-818, and particularly Bai@MOF-818 substantially attenuated the green fluorescence intensity, indicating their superior ROS scavenging capacity (Figures 3C and S7). The JC-1 mitochondrial membrane potential assessment revealed that OGD/R treatment caused severe mitochondrial dysfunction, with a significant decrease in red fluorescence and a corresponding increase in green fluorescence (Figure 3D). All treatment groups contributed to the membrane potential recovery; however, the Bai@MOF-818 composite system demonstrated the most remarkable protective effect (Figure S8). Excessive ROS accumulation induces oxidative stress, damages the mitochondria, and accelerates apoptosis. The decline in mitochondrial membrane potential is a critical marker of early apoptotic events. Effective ROS scavenging and restoration of the mitochondrial membrane potential can significantly mitigate oxidative damage and prevent apoptosis. In conclusion, Bai@MOF-818 demonstrated exceptional cytoprotective efficacy against OGD/R injury by efficiently scavenging intracellular ROS and stabilizing mitochondrial membrane potential while maintaining excellent biocompatibility. Fig. 3. Antioxidative effects of Bai@MOF-818. (A) Live/dead assays and (B) CCK-8 of PC-12 cells in different groups after culturing for 1day (n=3). (C) DCFH-DA staining of PC-12 cells. (D) JC-1 fluorescence staining of PC-12 cells (n=3). The data are presented as the mean ± sd. *p < 0.05, **p < 0.01. Immunomodulatory and anti-inflammatory effects in vitro To systematically evaluate the immunomodulatory and anti-inflammatory effects, changes in the expression of inflammation-related molecules were assessed at multiple biological levels. Immunofluorescence staining revealed that the expression of the M1 marker iNOS was significantly increased in BV2 microglia after OGD/R (Figures 4A-B), whereas the expression of the M2 marker Arg-1 was significantly suppressed (Figures 4C-D). These inflammatory changes were partially reversed by Bai or MOF-818 treatment alone, while Bai@MOF-818 significantly inhibited iNOS and upregulated Arg-1. Furthermore, Western blotting confirmed that Bai@MOF-818 significantly upregulated PPARγ and downregulated p-NF-κB and p-IκBα, with a phenotypic shift characterized by decreased CD86 and increased CD206 expression (Figures 4E–G). Q-PCR analysis revealed that Bai@MOF-818 significantly reduced the mRNA levels of pro-inflammatory factors IL-6 and TNF-α, while significantly increasing the mRNA expression of anti-inflammatory factors IL-10 and Arg-1, resulting in superior anti-inflammatory efficacy compared to all other groups (Figure S9). Bai@MOF-818 suppressed M1 responses and promoted M2 polarization by activating the PPARγ anti-inflammatory axis while inhibiting the NF-κB cascade, demonstrating superior immunomodulatory and anti-inflammatory efficacy under OGD/R. Fig. 4. Immunomodulatory and Anti-Inflammatory effects of Bai@MOF-818. (A) Immunofluorescence images of iNOS in BV-2 cells after OGD and 24h treatment (n=3). (B) Quantitative analysis of iNOS. (C) Immunofluorescence images of Arg-1 in BV-2 cells after OGD and 24h treatment (n=3). (D) Quantitative analysis of iNOS. (E) Western blot analysis of inflammation-related proteins in BV-2 cells after OGD and 24h treatment (n=3). (F) Quantitative analysis of PPARγ expression. (G) Quantitative analysis of p-NF-κB expression. The data are presented as the mean ± sd. *p < 0.05, **p < 0.01. Neuroprotective effects of Bai@MOF-818 in BV-2/PC-12 cells co-culture model Our previous studies demonstrated that Bai@MOF-818 can efficiently scavenge intracellular ROS in PC-12 cells and modulate BV-2 microglial polarization from the M1 to M2 phenotype while suppressing inflammatory responses. Based on these findings, a BV-2/PC-12 co-culture system was established to evaluate the protective effects against PC-12 cell apoptosis under OGD/R conditions. TUNEL staining results revealed that OGD/R induced PC-12 apoptosis, while Bai and MOF-818 alone only partially reduced TUNEL-positive rates, and the Bai@MOF-818 group exhibited a significant decrease in apoptotic cells with the most prominent protective effect (Figures 5A-B and S10). Western blot analysis revealed that OGD/R significantly upregulated Bax and cleaved-caspase-3 expression while downregulating Bcl-2, leading to a reduced Bcl-2/Bax ratio (Figures 5C–E). These alterations were effectively reversed by Bai@MOF-818 treatment, which restored Bcl-2/Bax balance and suppressed caspase-3 activation. These results indicate that Bai@MOF-818 could provide significant neuroprotection against hypoxia/reoxygenation injury in PC-12 cells by synergistically scavenging oxidative stress and modulating the immune microenvironment to prevent apoptosis. Fig. 5. Neuroprotective effects of Bai@MOF-818 in BV-2/PC-12 co-culture model. (A) Schematic diagram of BV-2/PC-12 co-culture system. (B) TUNEL staining of PC-12 cells after OGD and 24h treatment (n=3). (C) Western blot analysis of apoptosis-related proteins after OGD and 24h treatment (n=3). (D) Quantification of Bcl2/Bax ratio. (E) Quantification of cleaved-caspase3 expression. The data are presented as the mean ± sd. *p < 0.05, **p < 0.01. In vivo cerebral protection by Bai@MOF-818 in ischemic stroke To assess the in vivo neuroprotective efficacy of Bai@MOF-818, we induced left-hemisphere middle cerebral artery occlusion in SD rats. Following 1.5 h of ischemia, the therapeutic formulation was precisely injected into the ischemic core via stereotactic targeting using a Hamilton syringe, followed by 24 h of reperfusion. All rats underwent neurological assessment, followed by anesthesia for tissue collection and analysis (Figure 6A). TTC staining revealed a distinct cerebral infarct in the MCAO/R group, appearing as a white ischemic lesion (Figure 6B). Compared with the MCAO/R group, the Bai and MOF-818 treatment groups demonstrated partial neuroprotection, whereas the Bai@MOF-818 combination exerted the most pronounced effect, reducing the infarct size by approximately 25% (Figure 6D). Brain water content analysis revealed that MCAO/R significantly increased tissue hydration to approximately 85%. All treatments mitigated edema, with Bai@MOF-818 demonstrating the greatest reduction (Figure 6E). TUNEL staining revealed a significant increase in the number of apoptotic neurons after MCAO/R, indicating extensive apoptosis (Figure 6C). Bai@MOF-818 treatment substantially suppressed this apoptosis, reducing the percentage of TUNEL-positive cells to levels significantly lower than those achieved with either agent alone (Figure 6F). Hematoxylin eosin (HE) and Nissl staining revealed severe neuronal injury in the MCAO/R group, including abnormal morphology, increased necrotic cells, and significant loss of Nissl bodies (Figures 6G and I). Bai or MOF-818 monotherapy only partially alleviated these changes, whereas the Bai@MOF-818 combination improved neuroprotection, preserving neuronal structure, significantly reducing necrosis, and restoring Nissl body density (Figures 6H and J). These results demonstrate the synergistic effect of Bai@MOF-818 in mitigating cerebral ischemia-reperfusion (I/R) injury and protecting neurons. Behavioral assessments were performed 24 h after MCAO/R modeling using the cylinder test, Longa neurological deficit score, and adhesive removal test (Figure S11). These results demonstrated that MCAO/R significantly impaired motor coordination and sensorimotor function in rats. Treatment with only Bai or MOF-818 provided limited improvement, whereas Bai@MOF-818 combination therapy demonstrated outstanding performance in all three tests, significantly alleviating functional deficits caused by I/R, and demonstrating synergistic neuroprotective effects. Fig. 6. In Vivo Cerebral Protection by Bai@MOF-818 in Ischemic Stroke. (A) Schematic overview of the MCAO/R procedure and treatment timeline in rats. (B) TTC-stained coronal brain sections 1day post-MCAO/R. (C) Tunel staining and NeuN staining of the brain tissue (n=3). (D) Quantitative comparison of the infarct volume values for each treatment group (n=3). (E) Brain water content analysis (n=3). (F) Quantitative analysis of TUNEL-positive cell percentage (n=3). (G) HE staining of coronal sections from rats in the different treatment groups (n=3). H) Quantitative analysis of necrotic cell numbers in H&E staining. (I) Nissl staining of coronal sections. (J) Quantitative analysis of relative Nissl body density. The data are presented as the mean ± sd. *p < 0.05, **p < 0.01. Neuroprotective role of Bai@MOF-818 in MCAO/R rats To investigate the mechanism underlying the neuroprotective function of Bai@MOF-818, the following experiments were conducted. DHE staining results revealed that Bai@MOF-818 treatment significantly reduced MCAO/R-induced ROS accumulation, thereby alleviating oxidative damage (Figures 7A-B). Subsequent immunofluorescence staining for CD86/Iba1 (Figure 7C) and CD206/Iba1 (Figure 7E) revealed that cerebral ischemia induced the M1 polarization of microglia, as evidenced by increased CD86 expression (Figure 7D). The M2 phenotype marker, CD206, was significantly suppressed (Figure 7F), indicating a disrupted inflammatory microenvironment. Bai@MOF-818 effectively inhibited M1 polarization and promoted M2 polarization, implying its potential to reduce inflammation and facilitate tissue repair. Moreover, Q-PCR analysis revealed that Bai@MOF-818 significantly downregulated the transcription of pro-inflammatory cytokines (TNF-α and IL-6) while upregulating anti-inflammatory markers (Arg-1 and IL-10), confirming its regulatory role at the molecular level (Figure S12). In summary, Bai@MOF-818 exerts neuroprotective effects by scavenging ROS, modulating microglial polarization, and suppressing inflammatory responses, thereby establishing an immune microenvironment favorable for tissue recovery. Fig. 7. Antioxidative and Immunomodulatory effects in vivo. (A) DHE fluorescence staining of brain sections from each group. (B) Quantification of DHE fluorescence intensity (n=3). (C) Immunofluorescence images of CD86/Iba1. (D) Statistical analysis of CD86-positive microglia (n=3). (E) Immunofluorescence images of CD206/Iba1. (F) Statistical analysis of CD206-positive microglia (n=3). The data are presented as the mean ± sd. *p < 0.05, **p < 0.01. Biocompatibility of Bai@MOF-818 in vivo All treatment groups underwent in vivo biosafety evaluations. HE staining was performed to examine the histological structures of the heart, liver, spleen, and kidneys (Figure 8). No significant inflammatory infiltration or structural alterations were observed in any of the examined organs, demonstrating the biocompatibility of Bai@MOF-818. Fig. 8. H&E staining of the major organs from each group. Discussion Cerebral I/R injury is a complex, multistage pathological cascade characterized by excessive production of ROS, mitochondrial dysfunction, neuroinflammation, and neuronal apoptosis. The intricate interplay between these pathological processes often renders single-target therapies inadequate, thereby highlighting the urgent need for multifunctional nanoplatforms capable of orchestrating coordinated regulation across multiple pathological pathways. In this study, a Bai-loaded MOF-818 (Bai@MOF-818) nanosystem was developed to achieve carrier-drug synergy and enable multi-targeted intervention throughout the I/R process. On the one hand, MOF-818 possesses intrinsic SOD- and CAT-mimetic catalytic activities, allowing it to scavenge superoxide anions and hydrogen peroxide at the nanoscale, thereby rapidly reducing both intracellular and extracellular ROS levels. Notably, the catalytic decomposition of hydrogen peroxide by MOF-818 continuously generates molecular oxygen, effectively alleviating local hypoxia in the ischemic microenvironment. On the other hand, Bai exerts antioxidant effects by stimulating the expression of intrinsic antioxidant enzymes and simultaneously limiting the upstream generation of ROS, in addition to its notable anti-inflammatory properties [43]. MOF-818 was successfully synthesized and exhibited a highly ordered octahedral structure, large specific surface area, and well-defined mesoporous channels, as confirmed by SEM, XRD, and BET analyses. These structural features provide abundant loading sites and enable the efficient encapsulation of Bai. Drug-loading studies demonstrated that Bai@MOF-818 exhibited high loading capacity and encapsulation efficiency. Additionally, the pH-responsive release profile of MOF-818 ensures the selective and sustained release of Bai in the acidic microenvironment of ischemic tissues. This structural-functional design enabled Bai@MOF-818 to achieve high drug loading efficiency and sustained release, providing a reliable foundation for carrier-drug synergy in treating I/R injury. Under OGD/R conditions, Bai@MOF-818 demonstrated a robust antioxidant capacity. DCFH-DA staining demonstrated a significant reduction in intracellular ROS levels, indicating that the nanoformulation effectively decomposes excessive oxidative radicals generated during reperfusion injury. Concurrently, JC-1 assays revealed a significant increase in the red/green fluorescence ratio, indicating a preserved mitochondrial membrane potential and reduced mitochondrial depolarization. This stabilization of mitochondrial function is crucial as it prevents Cytochrome C release and downstream activation of the apoptotic cascade [44]. These findings imply that Bai@MOF-818 alleviates oxidative stress and disrupts mitochondrial dysfunction-driven cell death pathways, thereby providing comprehensive neuroprotection under ischemic conditions. Furthermore, OGD/R exposure significantly induced BV-2 microglial polarization toward the pro-inflammatory M1 phenotype, as evidenced by the upregulation of iNOS and CD86, as well as activation of the NF-κB signaling pathway. Conversely, treatment with Bai@MOF-818 promoted a phenotypic shift toward the anti-inflammatory M2 state, characterized by increased expression of Arg-1 and CD206, decreased phosphorylation of NF-κB and IκBα, and elevated PPARγ levels. These results suggest that Bai@MOF-818 promotes microglial polarization toward the anti-inflammatory M2 phenotype. This transition plays a critical role in regulating inflammatory signaling and supports immune microenvironment remodeling, ultimately enhancing neuroprotection during I/R injury. In the BV-2/PC-12 co-culture system subjected to OGD/R, Bai@MOF-818 demonstrated pronounced neuroprotective effects. TUNEL and western blotting results revealed reduced apoptosis in PC-12 cells, with fewer TUNEL-positive cells, suppressed Bax and cleaved caspase-3 levels, increased Bcl-2 expression, and restoration of the Bcl-2/Bax ratio. The neuroprotective effect of Bai@MOF-818 was primarily attributed to its dual regulation of oxidative stress and neuroinflammation. Bai@MOF-818 effectively scavenges intracellular ROS and stabilizes mitochondrial membrane potential, preventing mitochondrial dysfunction and inhibiting the mitochondria-mediated apoptotic pathway. Simultaneously, Bai@MOF-818 promoted microglial polarization toward the anti-inflammatory M2 phenotype, increased anti-inflammatory cytokine expression, and suppressed NF-κB-mediated pro-inflammatory signaling. These coordinated actions contribute to the remodeling of the neuroprotective immune microenvironment and ultimately support neuronal survival after I/R injury. In MCAO/R-induced rats, Bai@MOF-818 was stereotactically administered into the ischemic core, significantly increasing the local drug concentration and ensuring sustained drug retention and targeted delivery to the lesion site. TTC staining revealed that Bai@MOF-818 significantly reduced infarct volume, indicating its potent neuroprotective efficacy in limiting ischemic tissue damage. Additionally, brain water content measurements confirmed its effectiveness in mitigating cerebral edema and maintaining tissue fluid homeostasis, which not only alleviates intracranial pressure but also helps stabilize the local microenvironment, potentially preventing secondary injuries in the peri-infarct region and improving overall tissue viability. DHE fluorescence staining revealed that Bai@MOF-818 effectively scavenged excessive ROS in the ischemic brain tissue, thereby reducing oxidative stress. This antioxidative effect not only suppresses lipid peroxidation and mitochondrial damage but also prevents structural disruption of cellular membranes, preserves mitochondrial energy metabolism, and inhibits the persistent activation of ROS-mediated inflammatory signaling pathways, thereby interrupting the vicious pathological cycle between oxidative stress and inflammation [45]. H&E and Nissl staining, as well as NeuN/TUNEL double labeling, confirmed that Bai@MOF-818 preserved the structural integrity of brain tissue, attenuated neuronal loss, and significantly suppressed neuronal apoptosis. These combined effects suggest that Bai@MOF-818 can prevent the progression of ischemia-mediated structural damage and may facilitate the preservation of neurological function. Neurological function assessments consistently demonstrated significant improvements in the Bai@MOF-818 treatment group, which corresponded to the morphological protection observed in the brain tissues. These results indicate that the structural preservation provided by Bai@MOF-818 effectively translated into functional recovery, as evidenced by improvements in motor coordination, sensory performance, and overall behavioral function. These results demonstrated that Bai@MOF-818 maintained and amplified its synergistic antioxidative and immunomodulatory mechanisms under in vivo I/R conditions. By efficiently scavenging ROS and promoting microglial polarization toward the anti-inflammatory M2 phenotype, Bai@MOF-818 effectively alleviated ischemia-induced oxidative stress and neuroinflammation, disrupted the positive feedback loop between ROS accumulation and inflammatory cytokine release, and synergistically mitigated neuronal apoptosis and neuroinflammatory damage, ultimately facilitating neurological recovery. The safety evaluation revealed that Bai@MOF-818 failed to induce pathological alterations in major organs and exhibited no significant cytotoxicity in vitro , demonstrating its excellent biocompatibility and promising potential for clinical translation. In summary, our results demonstrated that the Bai@MOF-818 nanosystem is a robust multi-targeted therapeutic strategy for cerebral I/R injury, simultaneously regulating oxidative stress, neuroinflammation, and apoptosis. This platform combines catalytic and pharmacological functions to preserve neural structure and function while simultaneously laying a strong foundation for the clinical translation of nanomedicine in stroke therapy. Conclusion This study demonstrates that the Bai-loaded MOF-818 (Bai@MOF-818) nanosystem provides a promising multi-targeted therapeutic strategy for cerebral I/R injury. Bai@MOF-818 exhibits significant carrier–drug synergy, combining the catalytic properties of the MOF-818 framework with the pharmacological activities of Bai. Bai@MOF-818 efficiently scavenges ROS, preserves mitochondrial function, and promotes microglial polarization toward the anti-inflammatory M2 phenotype through this synergistic interaction. These coordinated effects alleviate oxidative stress, suppress neuroinflammation, and reduce neuronal apoptosis, thereby contributing to structural preservation and functional recovery. Overall, Bai@MOF-818 exhibits strong potential for clinical translation as a nanomedicine-based neuroprotective therapy for IS. Acknowledgements The illustration was partially created using BioRender.com. Funding This work was supported by Science and Technology Development Project of the Affiliated Hospital of Shandong Second Medical University (2023FYM026) and the National Natural Science Foundation of China (Grant No. 82003435), and the Natural Science Foundation of Shandong Province (Grant No. ZR2020QH332). Data availability All relevant data are available from the corresponding author upon reasonable request. Declarations Ethics approval and consent to participate All animal procedures were approved by the Ethics Committee of the Science and Technology Department of Linyi People’s Hospital (No：202409-A-007). Consent for publication All study participants provided informed consent for the publication of the research findings. 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Authors Affiliations Wei Shen Guangzhou University of Chinese Medicine View all articles by this author YuChen Wang Jinzhou Medical University View all articles by this author Xiaosong Zhu Linyi People's Hospital View all articles by this author Xiaojuan Chen Linyi People's Hospital View all articles by this author Xianjun Wang Linyi People's Hospital View all articles by this author Fengyuan Che [email protected] Guangzhou University of Chinese Medicine View all articles by this author Metrics & Citations Metrics Article Usage 169 views 93 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Wei Shen, YuChen Wang, Xiaosong Zhu, et al. Baicalin-Loaded MOF-818 Nanozyme for Ischemic Stroke Treatment via ROS Scavenging and Neuroinflammation Suppression. Authorea . 19 November 2025. DOI: https://doi.org/10.22541/au.176355580.02628044/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. 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