A Dual-Transformable MgGa-MOF Nanoplatform for HCC Therapy via Lactate Metabolism Blockade and Immune Reactivation

A Dual-Transformable MgGa-MOF Nanoplatform for HCC Therapy via Lactate Metabolism Blockade and Immune Reactivation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Method Article A Dual-Transformable MgGa-MOF Nanoplatform for HCC Therapy via Lactate Metabolism Blockade and Immune Reactivation yajie Li, yingying Wei, shaoshi Ma, feng li, xianwei Meng, shiping Yu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8600293/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Apr, 2026 Read the published version in Journal of Nanobiotechnology → Version 1 posted 10 You are reading this latest preprint version Abstract Microwave ablation (MWA) has emerged as one of the preferred modalities for treating hepatocellular carcinoma (HCC). However, its therapeutic efficiency is restricted by lactate accumulation after MWA. Lactate serves as a metabolic fuel for residual tumor cells, as well as acidifies the tumor microenvironment (TME) and impairs immune function, thereby fostering tumor recurrence and metastatic dissemination. Herein, we designed a dual-transformation strategy that turns metabolic fuel into waste and immunosuppressive pressure into power, implemented via bimetallic MOF-based nanoplatform (Dis@MgGa-MOF@TD/FA, DMGTF NCs), to counteract microwave-induced lactate elevation, reactivate immune activity and suppress primary tumor growth and metastatic progression. Specifically, after intravenous administration, folic acid (FA)-modified DMGTF accumulates in HCC, where microwave irradiation opens the 1-Tetradecanol (TD) gate to release diclofenac sodium (Dis). The released Dis suppresses MCT4-mediated lactate efflux, thereby disrupting lactate-driven energy supply and reshaping the TME. Meanwhile, microwave-activated DMGTF generates abundant ROS to impair mitochondrial lactate oxidation and collectively transforms metabolic "fuel" into biologically inert "waste". Moreover, framework-derived Mg²⁺ restarts T cells, boosts proliferation, and augments IFN-γ secretion, converting immunosuppressive "pressure" into antitumor "power". As a result, DMGTF NCs combined with MW achieve excellent therapeutic effects in a model of hepatocellular carcinoma and lung metastasis. This MOF-based dual-transformation strategy provides a promising solution to the long-standing challenge of post-MWA tumor relapse and dissemination, offering new insights into the effective control of liver cancer. Microwave therapy Microwave-responsive materials Immune metabolism Lactate metabolism modulation Immune reactivation Magnesium ions (Mg²⁺) Hepatocellular carcinoma Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 INTRODUCTION Hepatocellular carcinoma (HCC) is a major global health challenge, with an increasing number of deaths and new cases each year. Conventional therapies, mainly including surgery, radiotherapy and chemotherapy, are often limited by highly invasive procedures and associated side effects, highlighting the urgent need for novel therapeutic strategies 1 – 3 . Microwave ablation (MWA), as a type of clinical hyperthermia, offers minimal invasiveness, reduces side effects and shortens recovery time, making it a promising treatment method for HCC 4 , 5 . However, MWA is not sufficient to completely eliminate tumors, mainly due to the presence of sublethal zone created by intrinsic thermal gradient, in which residual cells survive thermal insult 6 – 8 . Studies have shown that these surviving cells undergo profound metabolic reprogramming, particularly an enhanced glycolytic flux that promotes the conversion of glucose to lactate, resulting in a marked increase in lactate levels 9 , 10 . Accumulated evidence implicates that the diverse and substantial influence of lactate in driving tumor recurrence and metastasis, especially in the context of microwave ablation 11 – 13 . Excess lactate not only serves as a fuel to sustain residual tumor cell proliferation but also contribute to the acidification of the tumor microenvironment (TME) 14 – 16 . This acidic microenvironment imposes substantial pressure on cytotoxic T cells, suppressing immune effector cell proliferation and inducing immune cell de-differentiation, to promote immune evasion and tumor spread 17 , 18 . Therefore, increasing efforts have been directed toward inhibiting lactate efflux in order to disrupt tumor metabolic adaptation and alleviate the immunosuppressive TME 19 – 21 . For example, a recent study by Qian and his colleagues demonstrated that Monocarboxylate Transporter 4 (MCT4) -mediated lactate export impairs antitumor immune responses 22 . Similarly, inhibition of MCT4 has been shown to reduce lactate efflux and enhance immune and oxidative stress responses in other carcinoma models 23 , 24 . However, inhibiting lactate efflux via MCT4 blockade fails to comprehensively disrupt tumor metabolism and reactivate immunodynamics 25 – 27 . First, even when lactate efflux is blocked, tumor cells can reroute intracellular lactate into mitochondrial metabolism, continuing to generate fuel and undermining the effectiveness of lactate-targeted interventions 28 , 29 . Furthermore, although extracellular lactate levels have been partially reduced, immune cells chronically exposed to a suppressive TME rarely regain full cytotoxic function, leading to incomplete immune reactivation and failure of antitumor immune surveillance 30 , 31 . Therefore, it is crucial to develop new strategies to comprehensively block lactate metabolism and restart dysfunctional immune cells in parallel with MWA. Given the dual challenge, we propose a dual-transformation strategy that converts metabolic fuel into waste and immunosuppressive pressure into immune power. Specifically, metal–organic frameworks (MOFs) were employed as microwave-sensitizing nanoplatforms 32 – 34 . On one hand, they facilitate the delivery of an MCT4 lactate transporter inhibitor to obstruct lactate efflux and disrupt intercellular energy transfer in tumor cells 35 , 36 . On the other hand, the microwave-responsive ROS generation of MOFs damages tumor cell mitochondria, inhibiting lactate oxidation and utilization 37 , 38 . This dual blockade effectively converts lactate from a metabolic fuel into a waste metabolite. Importantly, the metal ions within MOFs potentiate T cell proliferation and enhance effector functions, thereby transforming immunosuppressive pressure into immunostimulatory activity and eliciting systemic antitumor immunity 39 , 40 . As such, the introduction of MOF-based nanoplatforms provides a solid foundation for implementing the dual-transformation strategy, which may further address recurrence and metastasis in liver cancer. In this work, a liver-targeted, microwave-and pH-dual-responsive, degradable bimetallic metal–organic framework (Dis@MgGa-MOF@TD/FA, DMGTF NCs) has been constructed to co-deliver diclofenac sodium (Dis), the previously described MCT4 inhibitor. DMGTF NCs exhibits the following important advantages (Scheme 1 ): (1) Folic acid (FA) endows the nanoplatforms with liver cancer targeting and enhances cellular endocytosis ensuring preferential accumulation of DMGTF within tumor cells 41 – 43 . (2) 1-Tetradecanol (TD), forming the shell of DMGTF and serving as microwave thermal-responsive gate, enables controllable release of Dis under microwave irradiation, achieving precise delivery to tumor cells interiors 44 . (3) Dual-pathway lactate blockade is achieved, in which Dis inhibits MCT4-mediated lactate export and synergizes with microwave-induced ROS generated by Ga 3+ to damage mitochondrial function and block lactate oxidation, ultimately converting lactate from a tumor fuel into unusable metabolic waste and collapsing the survival foundation of residual tumor cells 45 , 46 . (4) Mg²⁺ reverses T-cell exhaustion, promotes proliferation, and enhances the secretion of effector molecules IFN-γ, thereby reactivating immune surveillance and inducing tumor cell killing 47 – 49 . DMGTF once again implements a transformation strategy that converts the immunosuppressive pressure of the TME into a driving force for potent antitumor immunity. Under microwave irradiation, DMGTF exhibits significant therapeutic effects in both liver cancer and lung metastasis models. Therefore, the successful construction of the dual-transformation nanoplatforms Dis@MgGa-MOF@TD/FA (DMGTF NCs) provides a paradigm for clinical to address tumor recurrence and metastasis after microwave treatment through effectively inhibiting tumor lactate metabolism, reactivating immune cell function, and inducing durable immune memory in vivo. RESULTS AND DISCUSSION Rationale for constructing DMGTF nanoplatform. We utilized MOF-based nanoplatforms to overcome the low bioavailability and poor tumor-targeting of lactate transporter inhibitors. To enhance tumor targeting and cellular uptake, folic acid (FA) was anchored onto the surface, while 1-tetradecanol (TD) was incorporated as a microwave-responsive switch to enable controlled release of diclofenac sodium (Dis). By carefully selecting the metal nodes and organic linkers, the MOFs were further tailored to integrate metabolic interference and immune regulation. Specifically, Ga³⁺ was incorporated to enhance microwave-triggered ROS generation, thereby inducing mitochondrial damage and further inhibiting lactate metabolism. Mg²⁺ provided excellent biocompatibility and modulated the immune microenvironment, promoting T cell activation and proliferation. Taken together, the Mg-Ga-MOF nanoplatforms functionalized with TD and FA constitute a multifunctional platform that enables the implementation of our dual-transformation strategy. Synthesis and Characterization of DMGTF. MgGa-MOF (MG) was synthesized via a hydrothermal route using Ga (NO) 3 · xH 2 O, Mg (NO₃) ₂·6H₂O, and terephthalic acid as precursors. Diclofenac sodium (Dis) was subsequently incorporated into MG through orbital shaking, yielding the formulation designated as DMG. Thereafter, 1-Tetradecanol (TD), serving as a microwave-responsive molecular switch, together with folic acid (FA), providing tumor-targeting capability, was anchored onto the DMG surface via a vacuum-assisted adsorption process to obtain the multifunctional nanoplatform, DMGTF NCs. SEM and TEM images revealed that the MG nanoparticles exhibited a uniform spherical morphology with a relatively homogeneous size distribution (Fig. 1 A, B). Dynamic light scattering (DLS) analysis showed a moderate increase in hydrodynamic diameter after surface modification, with the average size increasing from 176.6 nm to 256.5 nm (Fig. 1 C). Meanwhile, ζ-potential measurements displayed a pronounced shift in surface charge, with the values of 11.73mv for MG, -2.11mv for DMG, -5.82mv for DMGT, -12.47mv for DMGTF, collectively confirming the successful surface functionalization (Fig. 1 D). Energy-dispersive X-ray spectroscopy (EDS) confirmed the presence of Ga, Mg, C, and O elements with weight percentages of 15.78%, 14.22%, 49.14%, and 20.86%, respectively, verifying the successful incorporation of Mg and Ga into the MOF framework (Fig. 1 E). Fourier transform infrared (FTIR) spectra further validated the stepwise functionalization of DMGTF (Fig. 1 F). For pristine MgGa-MOF, characteristic bands at approximately 1535 cm⁻¹ and 1397 cm⁻¹ corresponded to the asymmetric and symmetric stretching vibrations of the coordinated carboxylate groups from terephthalic acid. After folic acid modification, an additional C = O stretching vibration (1600–1650 cm⁻¹) became discernible, leading to an overall enhancement and broadening of the absorption band within 1569–1689 cm⁻¹, confirming the successful conjugation of folic acid onto the MOF surface. Moreover, the emergence of the C-Cl stretching vibration of diclofenac sodium at 752 cm⁻¹ and the -CH₂- stretching band of 1-Tetradecanol (TD) at 2923 cm⁻¹ further verified the coexistence of both components in the final composite. X-Ray Diffraction (XRD) patterns indicated that MgGa-MOF retained a well-defined crystalline framework after modification (Fig. 1 G). Collectively, these results demonstrate the successful construction of the multifunctional nanoplatform DMGTF. Biodegradability Evaluation and Drug Release of MGTF. To assess environmental responsiveness, MG was dispersed in PBS at pH 7.4 and pH 5.7 to simulate physiological and TME, respectively. TEM imaging (Figure S1 ) revealed that the nanoparticles maintained stable morphology at pH 7.4 for up to 9 h. In contrast, under acidic conditions (pH 5.7), the number of intact nanoparticles gradually decreased from 3 h to 9 h, with evident structural degradation observed at 9 h, indicating acid-triggered biodegradability. Notably, microwave irradiation at pH 5.7 induced a rapid collapse of the spherical structure within 10 min and almost complete degradation after 30 min, demonstrating that microwave exposure further accelerates the breakdown of the 1-tetradecanol and MgGa-MOF, thereby enabling an effective microwave-triggered on–off release behavior. Diclofenac sodium (Dis), a lactate transporter inhibitor, was successfully encapsulated within DMGTF. UV-vis spectroscopy exhibited a characteristic absorption peak at 276 nm, which was used for quantitative calibration (Figure S2a, b). The encapsulation efficiency and drug loading capacity were calculated to be 34.4% and 20.5%, respectively. Drug release profiles (Fig. 1 H) demonstrated cumulative Dis release rates of 33.3% in neutral PBS, 81.5% in pH 5.7 PBS, and 98.1% in pH 5.7 + MW PBS conditions. Notably, after 6 h, the cumulative drug release under pH 5.7 + MW conditions were 10.3-fold and 5.75-fold higher, respectively, than under the neutral environment and pH 5.7 conditions, indicating clear microwave-and pH-dual-responsive release behavior. Further Evaluation of the Microwave Responsiveness of MgGa-MOF. A central objective of this work was to construct a metal-organic framework with both microwave heating and dynamic therapeutic functionalities as a foundation for noninvasive microwave therapy. The microwave dynamic effect of MgGa-MOF was investigated by monitoring reactive oxygen species (ROS) generation using DCFH-DA (Fig. 1 I). Minimal ROS signals were observed in the PBS and PBS + MW groups, while PBS + MG exhibited only a slight increase. In sharp contrast, the PBS + MG + MW group showed markedly enhanced ROS production, with fluorescence intensities 2.46-, 1.67-, and 1.64-fold higher than those of PBS, PBS + MW, and PBS + MG, respectively. Additionally, as shown in Fig. 1 J-L, the temperature rise displayed a clear positive correlation with particle concentration, reaching 23.05, 26.35, 31.60, and 37.06°C at 1, 5, 10, and 15 mg mL⁻¹, respectively, compared with 22.7°C for the control. The corresponding temperature differentials (0.35, 3.65, 8.90, and 14.36°C) confirmed a distinct concentration-dependent microwave heating effect, underscoring the excellent microwave-responsive capability of MgGa-MOF and its potential as a microwave hyperthermia agent. These findings demonstrate that MgGa-MOF can act both as a microwave sensitizer for microwave-induced heating and ROS generation, thereby enabling synergistic microwave thermal and dynamic therapeutic effects. Biocompatibility of MgGa-MOF. In vitro studies demonstrated that MgGa-MOF acts as a versatile microwave sensitizer with strong thermal and dynamic effects, while also serving as a pH-responsive drug carrier, underscoring its potential for tumor therapy. To further evaluate its biosafety, comprehensive biocompatibility studies were performed. Cytotoxicity assays showed that after 24 h of incubation with L929, H22, and HepG2 cells, the cell viabilities remained at 82.2%, 81.8%, and 80.5%, even at concentrations up to 200 µg mL⁻¹ (Fig. 2 A-C). In vivo acute toxicity tests in mice revealed no significant changes in body weight (Figure S3a) or hematological parameters (Figure S3b). The major organs (heart, kidney, liver, lung, and spleen) were collected for sectioning and hematoxylin and eosin (H&E) staining. No apparent lesions were observed in either the experimental groups (50 mg kg − 1,75 mg kg − 1, 100mg kg − 1) or the control group (Figure S4). Collectively, these results confirm the excellent biocompatibility and biosafety of MgGa-MOF both in vitro and in vivo, supporting its potential as a multifunctional therapeutic nanocarrier. Cellular Uptake and Tumor-Targeting Efficiency of DMGM. Encouraged by its excellent biosafety profile, the therapeutic performance of DMGTF was next evaluated in vitro. Considering that nanoparticle uptake depends on incubation time, endocytosis assays were conducted to identify the optimal internalization window. Rhodamine-loaded MgGa-MOF allowed fluorescence tracking, and confocal laser scanning microscopy revealed maximal intracellular accumulation at 6 h (Fig. 2 D), which was therefore used for subsequent experiments. Given that folic acid is a widely used targeting ligand due to the overexpression of folate receptors in hepatocellular carcinoma (HCC) cells compared to normal liver tissue, FA was successfully conjugated onto the MgGa-MOF surface to achieve tumor targeting41–43. Hyperspectral microscopy provided more detailed evidence confirming that FA significantly enhances cellular targeting. First, MgGa-MOF nanoparticles with or without FA modification were characterized to establish a spectral library for both nanomaterials (Fig. 2 F–Materials). This library was then applied to map the hyperspectral images of HepG-2 cells following nanoparticle internalization. In Fig. 2 F, HSI shows the hyperspectral images of cells incubated with the two nanoparticle formulations, whereas the HSI-Mapping panel uses red coloration to indicate the relative abundance of nanoparticles within the cells. The HSI-Overlay panel visualizes the spatial overlap between nanoparticle signals and cellular structures. After 6 h of incubation, both FA-modified (MGTF) and unmodified (MGT) nanoparticles were internalized; however, the mapped spectral intensity of MGTF was markedly higher, suggesting more efficient intracellular enrichment. This enhancement is attributed to FA-mediated receptor recognition and active endocytosis rather than passive uptake alone. Collectively, these findings demonstrate that FA conjugation endows MGTF with superior targeting capability toward hepatocellular carcinoma cells and significantly enhances cellular uptake, thereby providing a solid foundation for subsequent therapeutic investigations. In Vitro Therapeutic Performance of DMGTF. The therapeutic efficacy of DMGTF was evaluated in H22 and HepG2 cells under various treatment conditions (Fig. 2 E, S5 ). Seven groups were included: Control (G1), MW alone (G2), Dis (G3), MGTF (G4), MGTF + MW (G5), DMGTF(G6), and DMGTF + MW (G7). Using the control group (G1) as a reference, cell viability in the MGTF group (G4) remained highest among all treatments, consistent with earlier cytotoxicity results at 100µg mL⁻¹ (> 80%). MW treatment alone (G2) reduced viability to ~ 60% in both cell lines. In the Dis group (G3), H22 and HepG2 cells exhibited viabilities of 62.8% and 71.4%, respectively, likely reflecting differences in drug sensitivity. Notably, combining MGTF with MW (G5) further decreased cell viability to ~ 50%, highlighting the contribution of microwave stimulation. DMGTF treatment (G6) reduced viability to ~ 60%, whereas the addition of MW (G7) further decreased viability to ~ 35%, demonstrating a synergistic effect of the nanomaterial, drug, and microwave irradiation. Collectively, these results indicate that DMGTF exhibits potent cytotoxicity under microwave irradiation, effectively inducing apoptosis and supporting its potential for in vivo tumor therapy. Blocks Lactate Transport and Neutralizes the Acidic TME. As shown in Fig. 3 A, control cells exhibited basal MCT4 expression primarily localized on the plasma membrane and cytoplasm. Microwave (MW) exposure markedly enhanced MCT4 expression, consistent with MW-induced glycolytic activation. In contrast, both diclofenac sodium (Dis) and DMGTF treatments significantly suppressed MCT4 levels, with the most pronounced downregulation observed in the DMGTF + MW group. Consistent with these findings, lactate quantification (Fig. 3 B) revealed that MW irradiation increased lactate secretion, whereas Dis and DMGTF notably reduced lactate efflux. The DMGTF + MW combination achieved the lowest extracellular lactate concentration, confirming the effective blockade of lactate transport under MW stimulation. Restricting lactate efflux disrupts the intercellular metabolic exchange that normally functions as an energy shuttle, which in turn establishes the basis for converting lactate from a metabolic fuel into a metabolic waste. Medium pH measurements further substantiated these results. The control group showed a pH of 6.7, which decreased upon MW treatment due to accelerated metabolism. In contrast, Dis treatment increased pH to 7.0 by suppressing MCT4-mediated lactate export. DMGTF and DMGTF + MW groups exhibited further alkalization, reaching a pH of 7.7 in the latter (Fig. 3 C). This substantial neutralization of the acidic TME can be attributed to enhanced cellular uptake via FA-mediated targeting and efficient MCT4 inhibition induced by the drug-loaded MgGa-MOF under MW irradiation. DMGTF-Induced Mitochondrial Dysfunction Under Microwave Activation. Beyond blocking lactate efflux, converting lactate from a metabolic fuel into a waste product requires disrupting its mitochondrial utilization. DMGTF achieves this effect by inducing microwave-driven mitochondrial damage. Intracellular ROS generation was assessed using the DCFH-DA probe (Fig. 3 D) 50 . MW exposure alone elevated ROS levels, while both MGTF + MW and DMGTF + MW treatments produced stronger fluorescence signals, with DMGTF + MW showing the most intense ROS accumulation. In contrast, MGTF and DMGTF without MW irradiation exhibited weak fluorescence, underscoring the indispensable role of MW activation in amplifying oxidative stress. Mitochondrial membrane potential (ΔΨm) was subsequently evaluated by JC-1 staining (Fig. 3 E). Control, MW-only, and MGTF groups predominantly exhibited red fluorescence with minimal green signal, indicating intact mitochondrial function. Conversely, both MGTF + MW and DMGTF + MW groups showed markedly increased green fluorescence, signifying mitochondrial depolarization. Notably, partial retention of red fluorescence in the MGTF + MW group suggested transient hyperpolarization in some cells during MW stress. The DMGTF + MW group displayed the most pronounced decline in the red-to-green ratio, confirming severe mitochondrial damage and the strongest disruption of mitochondrial integrity. Collectively, these findings indicate that DMGTF, under MW irradiation, not only blocks extracellular lactate export but also suppresses mitochondrial energy metabolism through ROS-mediated depolarization, thereby reinforcing metabolic collapse in tumor cells. In this context, the metabolic pathway required for lactate oxidation is critically disrupted, further preventing its utilization and ultimately converting lactate from an energy substrate into an unusable metabolic waste. DMGTF Enhances Antitumor Immunity in a Tumor–Immune Cell Coculture System. A coculture model of HepG2 tumor cells and CTLL-2 immune cells was established to evaluate the dual effects of DMGTF on tumor inhibition and immune activation (Fig. 3 F). As shown in Fig. 3 G, in the absence of immune cells, tumor cells in the Control and Dis groups exhibited rapid proliferation, while MW, MGTF + MW, and DMGTF + MW treatments progressively inhibited cell growth, with DMGTF + MW showing the strongest suppression. Upon the introduction of CTLL-2 cells, tumor inhibition was further enhanced across all groups, which can be attributed to the combined cytotoxic effect of DMGTF on tumor cells and its immunostimulatory influence on T cells. Flow cytometric analysis of suspended CTLL-2 cells (Fig. 3 H) revealed a marked increase in immune cell proliferation, with the DMGTF + MW group reaching 375,912 cells per 300µL medium approximately a 7.6-fold increase compared with the control. The inhibition of tumor cells can be attributed partly to the direct cytotoxic effects of DMGTF, MW irradiation, and activated immune cells. More importantly, DMGTF not only induces tumor cell death but also promotes the proliferation of immune cells, thereby establishing a positive feedback loop that further amplifies the antitumor response. Furthermore, immunophenotyping demonstrated that T cell activation markers IFN-γ and CD69 (Fig. 3 I and Figure S6) were most strongly upregulated in the DMGTF + MW group, surpassing those in MW, Dis and MGTF group. Taken together, DMGTF under microwave irradiation exerts synergistic antitumor effects by suppressing lactate metabolism, inducing ROS-mediated mitochondrial dysfunction, and enhancing immune cell activation, thereby relieving tumor immunosuppression and amplifying therapeutic efficacy. These combined actions hold strong potential for preventing tumor recurrence and metastasis following microwave therapy. In Vivo Tumor Suppression of DMGTF. The in vivo antitumor efficacy of DMGTF was evaluated using an H22 subcutaneous syngeneic hepatocellular carcinoma model (Fig. 4 A). Mice were intravenously injected with different formulations at 50mg/kg, followed by microwave irradiation (1.8 W, 5 min) 6 h post-injection. As shown in Figs. 4 B-D, tumor temperatures increased by 25.9°C, 27.0°C, and 30.1°C in the MW, MGTF + MW, and DMGTF + MW groups, respectively. Statistical analysis of temperature elevation demonstrated that the DMGTF + MW group exhibited a significantly greater temperature rise than the MW group (p < 0.01), while both the MGTF + MW and DMGTF + MW groups showed markedly enhanced heating performance, confirming the pronounced microwave-sensitization effect of MgGa-MOF. Tumor growth curves (Fig. 4 E) revealed that the tumor volume in the DMGTF + MW group was markedly smaller than that in all other groups throughout the 14-day observation period. Owing to the aggressive proliferation of H22 tumors, several mice in the Control and Dis groups reached humane endpoints and were euthanized on day 10, while the DMGMF, MW-only and MGMF + MW groups were terminated on day 11 according to ethical requirements. Notably, only the DMGTF + MW group completed the full 14-day therapeutic schedule. Consistently, survival analysis (Fig. 4 F) demonstrated that DMGTF + MW treatment significantly prolonged survival compared with all other groups. These outcomes can be attributed to both the intrinsically high proliferative capacity of primary H22 tumors-resulting in slightly larger tumor sizes at baseline and the limited antitumor efficacy of Dis or MW alone, which neither eradicated tumors nor prevented recurrence. Similarly, DMGTF and MGTF without MW irradiation exhibited insufficient degradation and slow therapeutic onset, failing to restrain rapid tumor progression. In contrast, DMGTF under MW irradiation effectively eliminated tumor cells and suppressed tumor recurrence, enabling the most durable therapeutic benefit. Body weights remained stable throughout the study (Fig. 4 G), suggesting good biocompatibility and tolerability. Tumor-volume curves for individual mice (Fig. 4 H) further illustrate the growth trajectories, confirming that DMGTF + MW, compared with other groups, not only minimized tumor burden but also extended survival. Pulmonary Metastasis Inhibition by Microwave-Activated DMGTF . An H22 pulmonary metastasis model was established to evaluate the in vivo antitumor and survival efficacy of DMGTF (Fig. 5 A). Upon microwave irradiation, tumor temperatures increased by 25.1°C, 30.5°C, and 33.2°C in the MW, MGTF + MW, and DMGTF + MW groups, respectively (Figs. 5 B-D), consistent with the subcutaneous tumor results. As shown in Figs. 5 E and 5 F, mice were euthanized at different time points in accordance with ethical guidelines when tumor burden reached defined endpoints. Both MGTF + MW and DMGTF + MW treatments effectively suppressed tumor growth and significantly prolonged survival, with all mice in the DMGTF + MW group surviving the full 14 days and exhibiting the smallest tumor volumes. Mice in the Control and Dis groups reached humane endpoints and were euthanized on day 9, whereas the DMGTF and MW-only groups were terminated on day 10 according to ethical requirements. These outcomes reflect the limited antitumor efficacy of Dis or MW alone, which neither eradicated tumors nor prevented recurrence. Similarly, DMGTF and MGTF without MW irradiation showed incomplete degradation and slow therapeutic onset, failing to counteract rapid tumor progression. Individual tumor growth trajectories (Fig. 5 H) further confirmed that DMGTF + MW not only minimized tumor burden but also extended survival. Notably, while the MW-only group exhibited an initial reduction in tumor volume, rapid regrowth occurred after recurrence, highlighting the potential for tumor relapse following microwave therapy and emphasizing the need for combinatorial strategies to achieve durable treatment outcomes. Take together, these findings demonstrate that DMGTF, upon microwave activation, exhibits potent in vivo antitumor efficacy and markedly prolongs survival in H22-bearing mice. This effect can be attributed to the initial tumoricidal action of microwave irradiation, the dual blockade of tumor lactate metabolism mediated by diclofenac sodium and ROS, and the further cytotoxic contribution from immune cell activation induced by Mg²⁺. Antimetastatic and Immunomodulatory Effects of DMGTF. As shown in Figs. 6 A and Figures S7, the control group exhibited the largest number of pulmonary metastatic nodules, which were densely distributed and partially fused into plaques. Both the Dis and DMGTF groups showed reduced metastases to varying degrees; however, slightly larger nodules were observed in the DMGTF group, likely due to the absence of microwave activation that limited nanoplatform performance. In contrast, the MW, MGTF + MW, and particularly the DMGTF + MW groups displayed markedly fewer nodules, with almost no visible lesions in the DMGTF + MW group, confirming that DMGTF effectively mediates microwave-enhanced inhibition of pulmonary metastasis. To further assess immune modulation, tumor and spleen tissues were analyzed by flow cytometry for CD4⁺ and CD8⁺ T-cell populations. As shown in Figs. 6 B, C and 6 D, the DMGTF + MW group exhibited the highest proportions of CD4⁺ and CD8⁺ T cells, increasing by up to 1.42- and 1.65-fold relative to the control, respectively. Here, G1-G6 correspond to the Control, MW, Dis, DMGTF, MGTF + MW, and DMGTF + MW groups, respectively. Taken together, these findings indicate that microwave-activated DMGTF not only suppresses primary tumor growth but also leverages its immune-activating capacity to robustly promote CD8⁺ and CD4⁺ T-cell expansion, thereby transforming immunosuppressive pressure into effective antitumor immune drive and ultimately inhibiting distant pulmonary metastases. CONCLUSION In summary, we propose a dual-transformation strategy to address the challenging problem of tumor recurrence and metastasis microwave therapy. In this study, a microwave-and pH-dual-responsive, degradable MOF nanoplatform with liver-cancer-targeting capability has been developed to deliver diclofenac (Dis) and generate ROS for thoroughly disrupting tumor lactic-acid metabolism, transforming lactic acid from a metabolic fuel into metabolic waste. While simultaneously relieving the immunosuppressive TME, the released Mg²⁺ promotes T-cell proliferation and IFN-λ secretion, thereby reactivating antitumor immunity, inducing long-term immune memory, and converting immune suppression into immune activation. Although the direct regulatory role of Mg²⁺ on mitochondrial metabolism–driven T-cell proliferation was not fully delineated in this study, our findings suggest a positive association that warrants further investigation. Future work will focus on clarifying Mg²⁺-mediated metabolic remodeling in T cells, such as mitochondrial respiration, membrane potential, and ATP production. Comprehensive in vitro and in vivo studies confirmed that the DMGMG nanoplatform not only strategically overcomes the off-target limitations of traditional lactate-metabolism inhibitors, but also effectively suppresses tumor growth and metastasis through this dual strategy. Overall, this work provides a promising approach to resolving tumor recurrence and metastasis after microwave therapy and offers a new paradigm that integrates lactic-acid blockade with immune reactivation for future clinical applications. EXPERIMENTAL SECTION Materials. Gallium nitrate (Ga (NO₃) ₃, 99.99%) and polyvinylpyrrolidone (PVP) were purchased from Shanghai Macklin Biochemical Co., Ltd. Magnesium nitrate, terephthalic acid, and ammonia solution were obtained from Sa’en Chemical Technology Co., Ltd. N, N-dimethylformamide (DMF, 99.5%) and ethanol (99.7%) were supplied by Beijing Chemical Reagents Company. All reagents were used as received without further purification. Deionized water was used in all aqueous preparations. Animals. All animal experiments were approved by the Experimental Animal Management Committee of the Technical Institute of Physics and Chemistry, Chinese Academy of Sciences (IACUC-IPC-23013) and conducted in accordance with institutional guidelines for the care and use of laboratory animals. Female BALB/c mice (18 ± 2 g) were used for all in vivo studies. For establishing the subcutaneous tumor model, H22 hepatocellular carcinoma ascites cells (2 × 10⁷) were suspended in 100 µL DMEM and injected into the right axilla of each mouse. Tumor growth was monitored until volumes reached approximately 100 mm³, at which point in vivo therapeutic or metastasis experiments were initiated. Synthesis of MgGa-MOF Nanoparticles. MgGa-MOF nanoparticles were prepared via a solvothermal method. Gallium nitrate (22 mg), magnesium nitrate (7.1 mg), and PVP (100 mg) were dissolved in 10 mL DMF under sonication until a clear solution was obtained. Separately, 54 mg of terephthalic acid was dispersed in 10 mL DMF with ultrasonication. A mixture of 80 mL DMF and 30 µL ammonia solution was prepared, forming a milky suspension. The terephthalic acid solution was slowly added dropwise into the ammonia-containing DMF, during which the suspension gradually became lighter in color. Subsequently, the metal/PVP solution was added dropwise into the mixture, further lightening the suspension. An additional 100 mL of DMF was introduced, and the final solution was stirred thoroughly. The reaction mixture was transferred into a 50 mL Teflon-lined autoclave and heated at 150°C for 10 h. After cooling to room temperature, the precipitates were collected by centrifugation (10,000 rpm, 5 min), washed three times with ethanol to remove residual solvents and unreacted reagents, and dried to yield MgGa-MOF nanoparticles. Synthesis of Dis @MgGa-MOF and DMGTF Nanoparticles. For drug loading, MgGa-MOF (10 mg) was dispersed in 2 mL anhydrous ethanol, and diclofenac sodium (20 mg) was added. The mixture was stirred at room temperature for 6 h to allow efficient adsorption of the drug. The resulting Dis@MgGa-MOF nanoparticles were collected by centrifugation, washed three times with ethanol, and dried. To prepare DMGTF, Dis@MgGa-MOF nanoparticles (10 mg) were suspended in 2 mL anhydrous ethanol containing 1-tetradecanol (10 mg L⁻¹) under ultrasonication. Folic acid (1 mg) was dissolved in 3 mL methanol with ultrasonication, and 1 mL of this folic acid solution was added dropwise to the nanoparticle suspension. The mixture was ultrasonicated to ensure uniform coating and interaction. The solvent was removed under vacuum using a rotary evaporator, and the resulting yellowish-white powder was washed with deionized water, centrifuged at 10,000 rpm for 5 min, and collected as DMGTF nanoparticles. In Vitro Degradation. MGTF nanoparticles were dispersed in either saline or PBS (pH 5.7) to simulate physiological and tumor-like microenvironments, respectively. Suspensions were incubated at 37°C with gentle shaking. At predetermined time points (3, 6, and 9 h), nanoparticles were collected by centrifugation for characterization. For microwave-treated samples, additional collections were performed after 10, 20, and 30 min of irradiation. Morphological changes and structural integrity were examined using transmission electron microscopy (TEM) to assess degradation behavior under different conditions. Microwave-Responsive Thermal and Catalytic Properties. Nanoparticle suspensions (0–15 mg mL⁻¹) in 1 mL saline were transferred to quartz dishes and irradiated at 1.8 W for 5 min. Temperature changes were monitored using an infrared thermal imaging camera at 10 s intervals. To evaluate intracellular ROS generation, four groups were tested: PBS, MW, PBS + MGTF, and PBS + MGTF + MW. Materials were incubated with 1 mg mL⁻¹ MGTF for 1 h, and ROS levels were determined using DCFH-DA, with fluorescence intensity measured at 520 nm. Drug Release Study. Dis release from DMGTF nanoparticles (5 mg mL⁻¹) was investigated under three conditions: PBS pH 7.4, PBS pH 5.7, and PBS pH 5.7 with microwave irradiation (1.8 W, 5 min). Samples were incubated at 37°C in a shaking water bath. At 1, 3, 6, and 12 h, supernatants were collected after centrifugation and analyzed using UV-vis spectrophotometry at 276 nm. Cumulative drug release was calculated based on a standard calibration curve. In Vitro Cytotoxicity. L929, HepG2, and H22 cells were seeded in 96-well plates and treated with MGTF nanoparticles at concentrations of 0-200 µgmL⁻¹ for 24 h. Subsequently, 20µL of MTT solution was added, and cells were incubated for 4 h. The supernatant was removed, and 150µL DMSO was added to dissolve formazan crystals. Absorbance was measured using a microplate reader, and cell viability was calculated relative to untreated controls. In Vitro Therapeutic Evaluation. HepG2 and H22 cells were treated with seven groups (Control, MW, Dis, MGTF, MGTF + MW, DMGTF, DMGTF + MW) at 100µgmL⁻¹ for 24 h. Microwave groups were irradiated for 5 min and then reseeded into 96-well plates, while untreated groups were directly reseeded. Cell viability was assessed after 24 h using MTT and CCK-8 assays, measuring absorbance to evaluate the therapeutic effects of DMGTF with or without MW treatment. Cellular Internalization and Targeting. For internalization studies, MGTF nanoparticles were labeled with rhodamine and incubated with HepG2 cells (100µg mL⁻¹) for 3, 6, 9, and 12 h. Uptake was visualized using confocal laser scanning microscopy (CLSM). The targeting ability of DMGTF was evaluated by hyperspectral imaging. DMGT or DMGTF (1 mg/mL, 1µL) was deposited on glass coverslips and sealed to build spectral libraries using a Cytoviva push-broom system. HepG2 cells were seeded onto the coverslips and incubated with 100µg mL⁻¹ nanoparticles for 6 h, washed, fixed with 4% neutral formaldehyde, and imaged to assess folate-mediated cellular uptake. MCT4 Inhibition and Lactate/Extracellular pH Assays. HepG2 cells were treated with 100µg mL⁻¹ of control, MW, Dis, DMGTF or MGTF + MW, DMGTF + MW for 6 h. Cells were fixed in pre-chilled ethanol, permeabilized with 0.2% Triton X-100, blocked with 1% BSA for 1 h, and incubated with CL488-22787 primary antibody (1:200) for 1.5 h at room temperature. Fluorescence imaging was used to evaluate MCT4 expression. For lactate secretion, cells were treated similarly, and extracellular lactate was measured using a commercial assay kit. Extracellular pH of the medium was also recorded to assess the effect of DMGTF on TME acidity. Intracellular ROS and Mitochondrial Damage. Cells were treated with formulations (100µg mL⁻¹) for 6 h, and H₂O₂ (100µM) was used as a positive control. MW groups were irradiated for 5 min. ROS generation was measured using DCFH-DA, and mitochondrial membrane potential was assessed with 10µM JC-1 probe. Cells were washed and imaged under fluorescence microscopy to visualize mitochondrial integrity and oxidative stress. Co-Culture with Immune Cells. HepG2 cells were cultured alone or with CTLL-2 immune cells and treated with formulations as previously described. Scratch assays were performed at the time of treatment, and wound closure was observed after 48 h using fluorescence microscopy. CTLL-2 cells were analyzed by flow cytometry to quantify cell number and expression of IFN-γ and CD69, evaluating immune activation induced by DMGTF treatments. In Vivo Therapeutic Evaluation. Tumor-bearing mice (~ 100 mm³) were randomly assigned to six groups (control, MW, Dis, DMGTF, MGTF + MW, DMGTF + MW). Nanoparticles (100 mg·kg⁻¹) were administered intravenously. MW-treated groups received irradiation 6 h post-injection. Tumor volumes and body weights were monitored every day. At study endpoint, tumors and major organs were collected for histological analysis to evaluate treatment efficacy and biocompatibility. Declarations Author Contributions S.Y., and X.M. conceived the idea and supervised the research. Y.L. and Y.W. wrote and revised the manuscript. S.M. and F.L. helped check the data and provided valuable advice. All authors have approved the final version of the manuscript. Competing Interest The authors declare no competing financial interest. Ethics approval and consent to participate. All animal experiments have got permissions from the Institutional Animal Care and Use Committee (IACUC) guidelines of the Technical Institute of Physics and Chemistry (IPC) Animal Care (NO. IACUC-IPC-2506-011). Funding This work was supported by the National Natural Science Foundation of China (82172048, U21A20378), the Science and Education Cultivation Fund of the National Cancer and Regional Medical Center of Shanxi Provincial Cancer Hospital (TD2023003, BD2023004, QH2023013), the Science and Technology Cooperation and Exchange Special Project of Shanxi Province (202304041101030, 202304041101002), the Shanxi Center of Technology Innovation for Controlled and Sustained Release of Nano-drugs (202104010911026). Fundamental Research Program of Shanxi Province (202403021221305). Data availability All data are available in the main text, supporting information, and are also on request from the corresponding author. 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Supplementary Files SupplementaryInformationMgGaMOF.docx Cite Share Download PDF Status: Published Journal Publication published 05 Apr, 2026 Read the published version in Journal of Nanobiotechnology → Version 1 posted Editorial decision: Revision requested 30 Jan, 2026 Reviews received at journal 29 Jan, 2026 Reviewers agreed at journal 29 Jan, 2026 Reviews received at journal 28 Jan, 2026 Reviewers agreed at journal 26 Jan, 2026 Reviewers agreed at journal 26 Jan, 2026 Reviewers invited by journal 26 Jan, 2026 Editor assigned by journal 21 Jan, 2026 Submission checks completed at journal 21 Jan, 2026 First submitted to journal 14 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8600293","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Method Article","associatedPublications":[],"authors":[{"id":582008225,"identity":"fe3bccfe-0050-4bb7-b8df-573e085083ec","order_by":0,"name":"yajie Li","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"yajie","middleName":"","lastName":"Li","suffix":""},{"id":582008226,"identity":"7fd02da2-15ff-4d3b-af55-69c438ce53c5","order_by":1,"name":"yingying Wei","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"yingying","middleName":"","lastName":"Wei","suffix":""},{"id":582008227,"identity":"a4856ccd-0c21-4a40-9495-b61b0ab2d589","order_by":2,"name":"shaoshi Ma","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"shaoshi","middleName":"","lastName":"Ma","suffix":""},{"id":582008228,"identity":"efb9c7ae-3d71-4843-82cb-62b8147a978e","order_by":3,"name":"feng li","email":"","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"feng","middleName":"","lastName":"li","suffix":""},{"id":582008229,"identity":"04958972-93eb-482c-9744-69d204561c69","order_by":4,"name":"xianwei Meng","email":"","orcid":"","institution":"Chinese Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"xianwei","middleName":"","lastName":"Meng","suffix":""},{"id":582008230,"identity":"a10edfdf-31f4-4752-a91d-f9b963d80949","order_by":5,"name":"shiping Yu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4UlEQVRIiWNgGAWjYHACNoYEBgkGBvYGKP8A0Vp4YEqJ0gIGEglEajG4kf7swcMdFnnykc+fSd1sY5Dju5HA+LkAr5Ycc4PEMxLFhrdzjI1z2xiMJW8kMEvPwK+FTSKxTSJx4+wcxsdALYkbbiSwMfMQcBhEy8zjDw4DtdQToSXBDKxlvgSDIciWBANCWiTPvAFqOSORuIEH6JeccxKGM888bJbGp4XvePozyZ876hLntx9/Jp1TZiPPdzz54Gd8WhQOAAnGBqALD4D5ElAuHiDfAFUjj1/dKBgFo2AUjGQAABbCT4MrNLXcAAAAAElFTkSuQmCC","orcid":"","institution":"Shanxi Medical University","correspondingAuthor":true,"prefix":"","firstName":"shiping","middleName":"","lastName":"Yu","suffix":""}],"badges":[],"createdAt":"2026-01-14 09:53:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8600293/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8600293/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12951-026-04356-8","type":"published","date":"2026-04-05T15:59:55+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":101441828,"identity":"f7706c65-27f8-4b7a-b69a-8df48962b08f","added_by":"auto","created_at":"2026-01-29 17:13:58","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":480914,"visible":true,"origin":"","legend":"\u003cp\u003eCharacterization and Performance of DMGTF nanoplatforms. (A) SEM image of MG nanoparticles. (B) TEM image of MG nanoparticles. (C) Hydrodynamic diameter distributions of MG and MGTF nanoparticles. (D) ζ-Potential variations before and after surface modification. (E) Energy-dispersive X-ray spectroscopy (EDS) analysis of MGTF. (F) FTIR spectra of FA, TD, Dis, MG-MOF and DMGTF. (G) XRD pattern of MG. (H) Drug release profiles of DMGTF under various conditions. (I) Reactive oxygen species (ROS) generation of MG. (J) Microwave-induced temperature elevation curves of MG at different concentrations. (K) Temperature variations of MG under microwave irradiation. (L) Temperature increments of MG under different conditions. *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001 and ****p \u0026lt; 0.0001.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8600293/v1/ebd971ca683afc4748924575.jpg"},{"id":101441825,"identity":"24b1d369-f80e-48bc-a6f5-9ef543294e9a","added_by":"auto","created_at":"2026-01-29 17:13:58","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":425548,"visible":true,"origin":"","legend":"\u003cp\u003eIn vitro evaluation of DMGTF nanoplatforms. (A-C) Dose-dependent cytotoxicity of MGTF toward L929, H22, and HepG2 cells after 24 h incubation. (D) Confocal fluorescence microscopy images showing the time-dependent internalization of MGTF by cells. (E) Therapeutic efficacy of DMGTF nanoplatforms against tumor cells under different treatment conditions. (F) Hyperspectral imaging of MGT and MGTF after cellular incubation. *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001 and ****p \u0026lt; 0.0001.\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8600293/v1/f7b1c821b6f1fe6148da7c23.jpg"},{"id":101441830,"identity":"89dbc27d-ddb8-482b-ae01-136d3b63f7e3","added_by":"auto","created_at":"2026-01-29 17:13:58","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":450615,"visible":true,"origin":"","legend":"\u003cp\u003eIn vitro evaluation of DMGTF. (A) Immunofluorescence images of MCT4 protein (green) and Hoechst-stained nuclei (blue). (B) Extracellular lactate concentrations under different treatment conditions. (C) Extracellular pH under different treatments. (D) Fluorescence images showing intracellular ROS generation in HepG2 cells under various conditions. (E) Changes in mitochondrial membrane potential of HepG2 cells after different treatments. (F) Schematic illustration of DMGTF acting on HepG2 tumor cells and CTLL-2 immune cells. (G) Wound healing assay of HepG2 cells under different conditions. (H) Flow cytometry analysis of immune cell proliferation under various treatments. (I) Flow cytometry analysis of IFN-γ expression in CTLL-2 cells under different treatments. *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001 and ****p \u0026lt; 0.0001.\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8600293/v1/29ac20ee89a3cfae17359e40.jpg"},{"id":101751527,"identity":"ca70c8b9-1fb7-4075-b026-343da7f0d339","added_by":"auto","created_at":"2026-02-03 10:21:02","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":413450,"visible":true,"origin":"","legend":"\u003cp\u003eIn vivo evaluation of DMGTF nanoplatforms. (A) Schematic illustration of the experimental design using H22 tumor-bearing mice, in which the left-side tumor was designated as the primary tumor for treatment. (B) Temperature elevation profiles during MW irradiation. (C) Representative infrared thermal images recorded during MW exposure. (D) Average temperature increments among different groups. (E) Relative tumor growth curves after various treatments. (F) Survival rates of mice under each treatment condition. (G) Body-weight variations during the treatment period. (H) Tumor-volume curves for each group (n = 4). *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001 and ****p \u0026lt; 0.0001.\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8600293/v1/11d5e52018710de20e5470d0.jpg"},{"id":101441826,"identity":"267048d6-25d4-468d-97c1-54aecae32caf","added_by":"auto","created_at":"2026-01-29 17:13:58","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":402437,"visible":true,"origin":"","legend":"\u003cp\u003eIn vivo evaluation of DMGTF for lung metastatic tumor therapy. (A) Schematic illustration of the treatment strategy for metastatic tumors with DMGTF. (B) Temperature elevation curves of primary tumors during MW therapy. (C) Representative thermal images of primary tumors under MW irradiation. (D) Bar chart showing temperature differences among groups. (E) Relative growth curves of primary tumors after treatment. (F) Survival rates of mice under different treatments. (G) Body weight changes of mice after various treatments. (H) Tumor volume curves of each group (n = 4). *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001 and ****p \u0026lt; 0.0001.\u003c/p\u003e","description":"","filename":"Picture5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8600293/v1/ede267b8fbb0c3a3827e2fe4.jpg"},{"id":101441829,"identity":"952ca081-709b-4886-8bc0-b716e72c5974","added_by":"auto","created_at":"2026-01-29 17:13:58","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":405417,"visible":true,"origin":"","legend":"\u003cp\u003eIn vivo evaluation of DMGTF for metastatic tumor therapy. (A) Representative images of lungs collected from each treatment group. (B-C) Flow cytometric analysis of CD4⁺ and CD8⁺ T cells in spleens and cancer from each group (n = 3). (D) Quantitative comparison of CD4⁺/CD8⁺ T-cell populations in spleen and tumor tissues across different treatments. Data are presented as mean ± SD. *p \u0026lt; 0.05, **p \u0026lt; 0.01, ***p \u0026lt; 0.001 and ****p \u0026lt; 0.0001.\u003c/p\u003e","description":"","filename":"Picture6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8600293/v1/0e7244d8a5f4df30046e0b0b.jpg"},{"id":106343585,"identity":"b66a531c-c0e0-4698-add4-5478284f238c","added_by":"auto","created_at":"2026-04-07 16:06:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3475397,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8600293/v1/d8fdda5c-ad29-4b97-b75b-be868f3017e2.pdf"},{"id":101441832,"identity":"5e5e203a-eda3-4e78-8f48-e27b3cdad224","added_by":"auto","created_at":"2026-01-29 17:13:58","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":5882800,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryInformationMgGaMOF.docx","url":"https://assets-eu.researchsquare.com/files/rs-8600293/v1/bc9aab74f8bb36e044466bd4.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Dual-Transformable MgGa-MOF Nanoplatform for HCC Therapy via Lactate Metabolism Blockade and Immune Reactivation","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eHepatocellular carcinoma (HCC) is a major global health challenge, with an increasing number of deaths and new cases each year. Conventional therapies, mainly including surgery, radiotherapy and chemotherapy, are often limited by highly invasive procedures and associated side effects, highlighting the urgent need for novel therapeutic strategies\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Microwave ablation (MWA), as a type of clinical hyperthermia, offers minimal invasiveness, reduces side effects and shortens recovery time, making it a promising treatment method for HCC\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, MWA is not sufficient to completely eliminate tumors, mainly due to the presence of sublethal zone created by intrinsic thermal gradient, in which residual cells survive thermal insult\u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Studies have shown that these surviving cells undergo profound metabolic reprogramming, particularly an enhanced glycolytic flux that promotes the conversion of glucose to lactate, resulting in a marked increase in lactate levels\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAccumulated evidence implicates that the diverse and substantial influence of lactate in driving tumor recurrence and metastasis, especially in the context of microwave ablation\u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Excess lactate not only serves as a fuel to sustain residual tumor cell proliferation but also contribute to the acidification of the tumor microenvironment (TME) \u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. This acidic microenvironment imposes substantial pressure on cytotoxic T cells, suppressing immune effector cell proliferation and inducing immune cell de-differentiation, to promote immune evasion and tumor spread\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Therefore, increasing efforts have been directed toward inhibiting lactate efflux in order to disrupt tumor metabolic adaptation and alleviate the immunosuppressive TME\u003csup\u003e\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. For example, a recent study by Qian and his colleagues demonstrated that Monocarboxylate Transporter 4 (MCT4) -mediated lactate export impairs antitumor immune responses\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Similarly, inhibition of MCT4 has been shown to reduce lactate efflux and enhance immune and oxidative stress responses in other carcinoma models\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, inhibiting lactate efflux via MCT4 blockade fails to comprehensively disrupt tumor metabolism and reactivate immunodynamics\u003csup\u003e\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. First, even when lactate efflux is blocked, tumor cells can reroute intracellular lactate into mitochondrial metabolism, continuing to generate fuel and undermining the effectiveness of lactate-targeted interventions\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Furthermore, although extracellular lactate levels have been partially reduced, immune cells chronically exposed to a suppressive TME rarely regain full cytotoxic function, leading to incomplete immune reactivation and failure of antitumor immune surveillance\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Therefore, it is crucial to develop new strategies to comprehensively block lactate metabolism and restart dysfunctional immune cells in parallel with MWA.\u003c/p\u003e \u003cp\u003eGiven the dual challenge, we propose a dual-transformation strategy that converts metabolic fuel into waste and immunosuppressive pressure into immune power. Specifically, metal\u0026ndash;organic frameworks (MOFs) were employed as microwave-sensitizing nanoplatforms\u003csup\u003e\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. On one hand, they facilitate the delivery of an MCT4 lactate transporter inhibitor to obstruct lactate efflux and disrupt intercellular energy transfer in tumor cells\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. On the other hand, the microwave-responsive ROS generation of MOFs damages tumor cell mitochondria, inhibiting lactate oxidation and utilization\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. This dual blockade effectively converts lactate from a metabolic fuel into a waste metabolite. Importantly, the metal ions within MOFs potentiate T cell proliferation and enhance effector functions, thereby transforming immunosuppressive pressure into immunostimulatory activity and eliciting systemic antitumor immunity\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. As such, the introduction of MOF-based nanoplatforms provides a solid foundation for implementing the dual-transformation strategy, which may further address recurrence and metastasis in liver cancer.\u003c/p\u003e \u003cp\u003eIn this work, a liver-targeted, microwave-and pH-dual-responsive, degradable bimetallic metal\u0026ndash;organic framework (Dis@MgGa-MOF@TD/FA, DMGTF NCs) has been constructed to co-deliver diclofenac sodium (Dis), the previously described MCT4 inhibitor. DMGTF NCs exhibits the following important advantages (Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e): (1) Folic acid (FA) endows the nanoplatforms with liver cancer targeting and enhances cellular endocytosis ensuring preferential accumulation of DMGTF within tumor cells\u003csup\u003e\u003cspan additionalcitationids=\"CR42\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. (2) 1-Tetradecanol (TD), forming the shell of DMGTF and serving as microwave thermal-responsive gate, enables controllable release of Dis under microwave irradiation, achieving precise delivery to tumor cells interiors\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. (3) Dual-pathway lactate blockade is achieved, in which Dis inhibits MCT4-mediated lactate export and synergizes with microwave-induced ROS generated by Ga\u003csup\u003e3+\u003c/sup\u003e to damage mitochondrial function and block lactate oxidation, ultimately converting lactate from a tumor fuel into unusable metabolic waste and collapsing the survival foundation of residual tumor cells\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. (4) Mg\u0026sup2;⁺ reverses T-cell exhaustion, promotes proliferation, and enhances the secretion of effector molecules IFN-γ, thereby reactivating immune surveillance and inducing tumor cell killing\u003csup\u003e\u003cspan additionalcitationids=\"CR48\" citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e. DMGTF once again implements a transformation strategy that converts the immunosuppressive pressure of the TME into a driving force for potent antitumor immunity. Under microwave irradiation, DMGTF exhibits significant therapeutic effects in both liver cancer and lung metastasis models. Therefore, the successful construction of the dual-transformation nanoplatforms Dis@MgGa-MOF@TD/FA (DMGTF NCs) provides a paradigm for clinical to address tumor recurrence and metastasis after microwave treatment through effectively inhibiting tumor lactate metabolism, reactivating immune cell function, and inducing durable immune memory in vivo.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"RESULTS AND DISCUSSION","content":"\u003cp\u003e \u003cb\u003eRationale for constructing DMGTF nanoplatform.\u003c/b\u003e We utilized MOF-based nanoplatforms to overcome the low bioavailability and poor tumor-targeting of lactate transporter inhibitors. To enhance tumor targeting and cellular uptake, folic acid (FA) was anchored onto the surface, while 1-tetradecanol (TD) was incorporated as a microwave-responsive switch to enable controlled release of diclofenac sodium (Dis). By carefully selecting the metal nodes and organic linkers, the MOFs were further tailored to integrate metabolic interference and immune regulation. Specifically, Ga\u0026sup3;⁺ was incorporated to enhance microwave-triggered ROS generation, thereby inducing mitochondrial damage and further inhibiting lactate metabolism. Mg\u0026sup2;⁺ provided excellent biocompatibility and modulated the immune microenvironment, promoting T cell activation and proliferation. Taken together, the Mg-Ga-MOF nanoplatforms functionalized with TD and FA constitute a multifunctional platform that enables the implementation of our dual-transformation strategy.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSynthesis and Characterization of DMGTF.\u003c/b\u003e MgGa-MOF (MG) was synthesized via a hydrothermal route using Ga (NO)\u003csub\u003e3\u003c/sub\u003e\u0026middot; xH\u003csub\u003e2\u003c/sub\u003eO, Mg (NO₃) ₂\u0026middot;6H₂O, and terephthalic acid as precursors. Diclofenac sodium (Dis) was subsequently incorporated into MG through orbital shaking, yielding the formulation designated as DMG. Thereafter, 1-Tetradecanol (TD), serving as a microwave-responsive molecular switch, together with folic acid (FA), providing tumor-targeting capability, was anchored onto the DMG surface via a vacuum-assisted adsorption process to obtain the multifunctional nanoplatform, DMGTF NCs. SEM and TEM images revealed that the MG nanoparticles exhibited a uniform spherical morphology with a relatively homogeneous size distribution (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA, B). Dynamic light scattering (DLS) analysis showed a moderate increase in hydrodynamic diameter after surface modification, with the average size increasing from 176.6 nm to 256.5 nm (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). Meanwhile, ζ-potential measurements displayed a pronounced shift in surface charge, with the values of 11.73mv for MG, -2.11mv for DMG, -5.82mv for DMGT, -12.47mv for DMGTF, collectively confirming the successful surface functionalization (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). Energy-dispersive X-ray spectroscopy (EDS) confirmed the presence of Ga, Mg, C, and O elements with weight percentages of 15.78%, 14.22%, 49.14%, and 20.86%, respectively, verifying the successful incorporation of Mg and Ga into the MOF framework (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE). Fourier transform infrared (FTIR) spectra further validated the stepwise functionalization of DMGTF (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF). For pristine MgGa-MOF, characteristic bands at approximately 1535 cm⁻\u0026sup1; and 1397 cm⁻\u0026sup1; corresponded to the asymmetric and symmetric stretching vibrations of the coordinated carboxylate groups from terephthalic acid. After folic acid modification, an additional C\u0026thinsp;=\u0026thinsp;O stretching vibration (1600\u0026ndash;1650 cm⁻\u0026sup1;) became discernible, leading to an overall enhancement and broadening of the absorption band within 1569\u0026ndash;1689 cm⁻\u0026sup1;, confirming the successful conjugation of folic acid onto the MOF surface. Moreover, the emergence of the C-Cl stretching vibration of diclofenac sodium at 752 cm⁻\u0026sup1; and the -CH₂- stretching band of 1-Tetradecanol (TD) at 2923 cm⁻\u0026sup1; further verified the coexistence of both components in the final composite. X-Ray Diffraction (XRD) patterns indicated that MgGa-MOF retained a well-defined crystalline framework after modification (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eG). Collectively, these results demonstrate the successful construction of the multifunctional nanoplatform DMGTF.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eBiodegradability Evaluation and Drug Release of MGTF.\u003c/b\u003e To assess environmental responsiveness, MG was dispersed in PBS at pH 7.4 and pH 5.7 to simulate physiological and TME, respectively. TEM imaging (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e) revealed that the nanoparticles maintained stable morphology at pH 7.4 for up to 9 h. In contrast, under acidic conditions (pH 5.7), the number of intact nanoparticles gradually decreased from 3 h to 9 h, with evident structural degradation observed at 9 h, indicating acid-triggered biodegradability. Notably, microwave irradiation at pH 5.7 induced a rapid collapse of the spherical structure within 10 min and almost complete degradation after 30 min, demonstrating that microwave exposure further accelerates the breakdown of the 1-tetradecanol and MgGa-MOF, thereby enabling an effective microwave-triggered on\u0026ndash;off release behavior.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDiclofenac sodium (Dis), a lactate transporter inhibitor, was successfully encapsulated within DMGTF. UV-vis spectroscopy exhibited a characteristic absorption peak at 276 nm, which was used for quantitative calibration (Figure S2a, b). The encapsulation efficiency and drug loading capacity were calculated to be 34.4% and 20.5%, respectively. Drug release profiles (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eH) demonstrated cumulative Dis release rates of 33.3% in neutral PBS, 81.5% in pH 5.7 PBS, and 98.1% in pH 5.7\u0026thinsp;+\u0026thinsp;MW PBS conditions. Notably, after 6 h, the cumulative drug release under pH 5.7\u0026thinsp;+\u0026thinsp;MW conditions were 10.3-fold and 5.75-fold higher, respectively, than under the neutral environment and pH 5.7 conditions, indicating clear microwave-and pH-dual-responsive release behavior.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eFurther Evaluation of the Microwave Responsiveness of MgGa-MOF.\u003c/b\u003e A central objective of this work was to construct a metal-organic framework with both microwave heating and dynamic therapeutic functionalities as a foundation for noninvasive microwave therapy. The microwave dynamic effect of MgGa-MOF was investigated by monitoring reactive oxygen species (ROS) generation using DCFH-DA (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eI). Minimal ROS signals were observed in the PBS and PBS\u0026thinsp;+\u0026thinsp;MW groups, while PBS\u0026thinsp;+\u0026thinsp;MG exhibited only a slight increase. In sharp contrast, the PBS\u0026thinsp;+\u0026thinsp;MG\u0026thinsp;+\u0026thinsp;MW group showed markedly enhanced ROS production, with fluorescence intensities 2.46-, 1.67-, and 1.64-fold higher than those of PBS, PBS\u0026thinsp;+\u0026thinsp;MW, and PBS\u0026thinsp;+\u0026thinsp;MG, respectively. Additionally, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eJ-L, the temperature rise displayed a clear positive correlation with particle concentration, reaching 23.05, 26.35, 31.60, and 37.06\u0026deg;C at 1, 5, 10, and 15 mg mL⁻\u0026sup1;, respectively, compared with 22.7\u0026deg;C for the control. The corresponding temperature differentials (0.35, 3.65, 8.90, and 14.36\u0026deg;C) confirmed a distinct concentration-dependent microwave heating effect, underscoring the excellent microwave-responsive capability of MgGa-MOF and its potential as a microwave hyperthermia agent. These findings demonstrate that MgGa-MOF can act both as a microwave sensitizer for microwave-induced heating and ROS generation, thereby enabling synergistic microwave thermal and dynamic therapeutic effects.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eBiocompatibility of MgGa-MOF.\u003c/b\u003e In vitro studies demonstrated that MgGa-MOF acts as a versatile microwave sensitizer with strong thermal and dynamic effects, while also serving as a pH-responsive drug carrier, underscoring its potential for tumor therapy. To further evaluate its biosafety, comprehensive biocompatibility studies were performed. Cytotoxicity assays showed that after 24 h of incubation with L929, H22, and HepG2 cells, the cell viabilities remained at 82.2%, 81.8%, and 80.5%, even at concentrations up to 200 \u0026micro;g mL⁻\u0026sup1; (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eA-C). In vivo acute toxicity tests in mice revealed no significant changes in body weight (Figure S3a) or hematological parameters (Figure S3b). The major organs (heart, kidney, liver, lung, and spleen) were collected for sectioning and hematoxylin and eosin (H\u0026amp;E) staining. No apparent lesions were observed in either the experimental groups (50 mg kg\u0026thinsp;\u0026minus;\u0026thinsp;1,75 mg kg\u0026thinsp;\u0026minus;\u0026thinsp;1, 100mg kg\u0026thinsp;\u0026minus;\u0026thinsp;1) or the control group (Figure S4). Collectively, these results confirm the excellent biocompatibility and biosafety of MgGa-MOF both in vitro and in vivo, supporting its potential as a multifunctional therapeutic nanocarrier.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCellular Uptake and Tumor-Targeting Efficiency of DMGM. Encouraged by its excellent biosafety profile, the therapeutic performance of DMGTF was next evaluated in vitro. Considering that nanoparticle uptake depends on incubation time, endocytosis assays were conducted to identify the optimal internalization window. Rhodamine-loaded MgGa-MOF allowed fluorescence tracking, and confocal laser scanning microscopy revealed maximal intracellular accumulation at 6 h (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eD), which was therefore used for subsequent experiments. Given that folic acid is a widely used targeting ligand due to the overexpression of folate receptors in hepatocellular carcinoma (HCC) cells compared to normal liver tissue, FA was successfully conjugated onto the MgGa-MOF surface to achieve tumor targeting41\u0026ndash;43. Hyperspectral microscopy provided more detailed evidence confirming that FA significantly enhances cellular targeting. First, MgGa-MOF nanoparticles with or without FA modification were characterized to establish a spectral library for both nanomaterials (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eF\u0026ndash;Materials). This library was then applied to map the hyperspectral images of HepG-2 cells following nanoparticle internalization. In Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eF, HSI shows the hyperspectral images of cells incubated with the two nanoparticle formulations, whereas the HSI-Mapping panel uses red coloration to indicate the relative abundance of nanoparticles within the cells. The HSI-Overlay panel visualizes the spatial overlap between nanoparticle signals and cellular structures. After 6 h of incubation, both FA-modified (MGTF) and unmodified (MGT) nanoparticles were internalized; however, the mapped spectral intensity of MGTF was markedly higher, suggesting more efficient intracellular enrichment. This enhancement is attributed to FA-mediated receptor recognition and active endocytosis rather than passive uptake alone. Collectively, these findings demonstrate that FA conjugation endows MGTF with superior targeting capability toward hepatocellular carcinoma cells and significantly enhances cellular uptake, thereby providing a solid foundation for subsequent therapeutic investigations.\u003c/p\u003e \u003cp\u003eIn Vitro Therapeutic Performance of DMGTF. The therapeutic efficacy of DMGTF was evaluated in H22 and HepG2 cells under various treatment conditions (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eE, \u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003eS5\u003c/span\u003e). Seven groups were included: Control (G1), MW alone (G2), Dis (G3), MGTF (G4), MGTF\u0026thinsp;+\u0026thinsp;MW (G5), DMGTF(G6), and DMGTF\u0026thinsp;+\u0026thinsp;MW (G7). Using the control group (G1) as a reference, cell viability in the MGTF group (G4) remained highest among all treatments, consistent with earlier cytotoxicity results at 100\u0026micro;g mL⁻\u0026sup1; (\u0026gt;\u0026thinsp;80%). MW treatment alone (G2) reduced viability to ~\u0026thinsp;60% in both cell lines. In the Dis group (G3), H22 and HepG2 cells exhibited viabilities of 62.8% and 71.4%, respectively, likely reflecting differences in drug sensitivity. Notably, combining MGTF with MW (G5) further decreased cell viability to ~\u0026thinsp;50%, highlighting the contribution of microwave stimulation. DMGTF treatment (G6) reduced viability to ~\u0026thinsp;60%, whereas the addition of MW (G7) further decreased viability to ~\u0026thinsp;35%, demonstrating a synergistic effect of the nanomaterial, drug, and microwave irradiation. Collectively, these results indicate that DMGTF exhibits potent cytotoxicity under microwave irradiation, effectively inducing apoptosis and supporting its potential for in vivo tumor therapy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eBlocks Lactate Transport and Neutralizes the Acidic TME.\u003c/b\u003e As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, control cells exhibited basal MCT4 expression primarily localized on the plasma membrane and cytoplasm. Microwave (MW) exposure markedly enhanced MCT4 expression, consistent with MW-induced glycolytic activation. In contrast, both diclofenac sodium (Dis) and DMGTF treatments significantly suppressed MCT4 levels, with the most pronounced downregulation observed in the DMGTF\u0026thinsp;+\u0026thinsp;MW group. Consistent with these findings, lactate quantification (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e3\u003c/span\u003eB) revealed that MW irradiation increased lactate secretion, whereas Dis and DMGTF notably reduced lactate efflux. The DMGTF\u0026thinsp;+\u0026thinsp;MW combination achieved the lowest extracellular lactate concentration, confirming the effective blockade of lactate transport under MW stimulation. Restricting lactate efflux disrupts the intercellular metabolic exchange that normally functions as an energy shuttle, which in turn establishes the basis for converting lactate from a metabolic fuel into a metabolic waste. Medium pH measurements further substantiated these results. The control group showed a pH of 6.7, which decreased upon MW treatment due to accelerated metabolism. In contrast, Dis treatment increased pH to 7.0 by suppressing MCT4-mediated lactate export. DMGTF and DMGTF\u0026thinsp;+\u0026thinsp;MW groups exhibited further alkalization, reaching a pH of 7.7 in the latter (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e3\u003c/span\u003eC). This substantial neutralization of the acidic TME can be attributed to enhanced cellular uptake via FA-mediated targeting and efficient MCT4 inhibition induced by the drug-loaded MgGa-MOF under MW irradiation.\u003c/p\u003e \u003cp\u003e \u003cb\u003eDMGTF-Induced Mitochondrial Dysfunction Under Microwave Activation.\u003c/b\u003e Beyond blocking lactate efflux, converting lactate from a metabolic fuel into a waste product requires disrupting its mitochondrial utilization. DMGTF achieves this effect by inducing microwave-driven mitochondrial damage. Intracellular ROS generation was assessed using the DCFH-DA probe (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e3\u003c/span\u003eD)\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e. MW exposure alone elevated ROS levels, while both MGTF\u0026thinsp;+\u0026thinsp;MW and DMGTF\u0026thinsp;+\u0026thinsp;MW treatments produced stronger fluorescence signals, with DMGTF\u0026thinsp;+\u0026thinsp;MW showing the most intense ROS accumulation. In contrast, MGTF and DMGTF without MW irradiation exhibited weak fluorescence, underscoring the indispensable role of MW activation in amplifying oxidative stress. Mitochondrial membrane potential (ΔΨm) was subsequently evaluated by JC-1 staining (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e3\u003c/span\u003eE). Control, MW-only, and MGTF groups predominantly exhibited red fluorescence with minimal green signal, indicating intact mitochondrial function. Conversely, both MGTF\u0026thinsp;+\u0026thinsp;MW and DMGTF\u0026thinsp;+\u0026thinsp;MW groups showed markedly increased green fluorescence, signifying mitochondrial depolarization. Notably, partial retention of red fluorescence in the MGTF\u0026thinsp;+\u0026thinsp;MW group suggested transient hyperpolarization in some cells during MW stress. The DMGTF\u0026thinsp;+\u0026thinsp;MW group displayed the most pronounced decline in the red-to-green ratio, confirming severe mitochondrial damage and the strongest disruption of mitochondrial integrity. Collectively, these findings indicate that DMGTF, under MW irradiation, not only blocks extracellular lactate export but also suppresses mitochondrial energy metabolism through ROS-mediated depolarization, thereby reinforcing metabolic collapse in tumor cells. In this context, the metabolic pathway required for lactate oxidation is critically disrupted, further preventing its utilization and ultimately converting lactate from an energy substrate into an unusable metabolic waste.\u003c/p\u003e \u003cp\u003e \u003cb\u003eDMGTF Enhances Antitumor Immunity in a Tumor\u0026ndash;Immune Cell Coculture System.\u003c/b\u003e A coculture model of HepG2 tumor cells and CTLL-2 immune cells was established to evaluate the dual effects of DMGTF on tumor inhibition and immune activation (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e3\u003c/span\u003eF). As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e3\u003c/span\u003eG, in the absence of immune cells, tumor cells in the Control and Dis groups exhibited rapid proliferation, while MW, MGTF\u0026thinsp;+\u0026thinsp;MW, and DMGTF\u0026thinsp;+\u0026thinsp;MW treatments progressively inhibited cell growth, with DMGTF\u0026thinsp;+\u0026thinsp;MW showing the strongest suppression. Upon the introduction of CTLL-2 cells, tumor inhibition was further enhanced across all groups, which can be attributed to the combined cytotoxic effect of DMGTF on tumor cells and its immunostimulatory influence on T cells. Flow cytometric analysis of suspended CTLL-2 cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e3\u003c/span\u003eH) revealed a marked increase in immune cell proliferation, with the DMGTF\u0026thinsp;+\u0026thinsp;MW group reaching 375,912 cells per 300\u0026micro;L medium approximately a 7.6-fold increase compared with the control. The inhibition of tumor cells can be attributed partly to the direct cytotoxic effects of DMGTF, MW irradiation, and activated immune cells. More importantly, DMGTF not only induces tumor cell death but also promotes the proliferation of immune cells, thereby establishing a positive feedback loop that further amplifies the antitumor response. Furthermore, immunophenotyping demonstrated that T cell activation markers IFN-γ and CD69 (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e3\u003c/span\u003eI and Figure S6) were most strongly upregulated in the DMGTF\u0026thinsp;+\u0026thinsp;MW group, surpassing those in MW, Dis and MGTF group. Taken together, DMGTF under microwave irradiation exerts synergistic antitumor effects by suppressing lactate metabolism, inducing ROS-mediated mitochondrial dysfunction, and enhancing immune cell activation, thereby relieving tumor immunosuppression and amplifying therapeutic efficacy. These combined actions hold strong potential for preventing tumor recurrence and metastasis following microwave therapy.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e\u003cb\u003eIn Vivo Tumor Suppression of DMGTF.\u003c/b\u003e The in vivo antitumor efficacy of DMGTF was evaluated using an H22 subcutaneous syngeneic hepatocellular carcinoma model (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). Mice were intravenously injected with different formulations at 50mg/kg, followed by microwave irradiation (1.8 W, 5 min) 6 h post-injection. As shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e4\u003c/span\u003eB-D, tumor temperatures increased by 25.9\u0026deg;C, 27.0\u0026deg;C, and 30.1\u0026deg;C in the MW, MGTF\u0026thinsp;+\u0026thinsp;MW, and DMGTF\u0026thinsp;+\u0026thinsp;MW groups, respectively. Statistical analysis of temperature elevation demonstrated that the DMGTF\u0026thinsp;+\u0026thinsp;MW group exhibited a significantly greater temperature rise than the MW group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), while both the MGTF\u0026thinsp;+\u0026thinsp;MW and DMGTF\u0026thinsp;+\u0026thinsp;MW groups showed markedly enhanced heating performance, confirming the pronounced microwave-sensitization effect of MgGa-MOF. Tumor growth curves (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e4\u003c/span\u003eE) revealed that the tumor volume in the DMGTF\u0026thinsp;+\u0026thinsp;MW group was markedly smaller than that in all other groups throughout the 14-day observation period. Owing to the aggressive proliferation of H22 tumors, several mice in the Control and Dis groups reached humane endpoints and were euthanized on day 10, while the DMGMF, MW-only and MGMF\u0026thinsp;+\u0026thinsp;MW groups were terminated on day 11 according to ethical requirements. Notably, only the DMGTF\u0026thinsp;+\u0026thinsp;MW group completed the full 14-day therapeutic schedule. Consistently, survival analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e4\u003c/span\u003eF) demonstrated that DMGTF\u0026thinsp;+\u0026thinsp;MW treatment significantly prolonged survival compared with all other groups. These outcomes can be attributed to both the intrinsically high proliferative capacity of primary H22 tumors-resulting in slightly larger tumor sizes at baseline and the limited antitumor efficacy of Dis or MW alone, which neither eradicated tumors nor prevented recurrence. Similarly, DMGTF and MGTF without MW irradiation exhibited insufficient degradation and slow therapeutic onset, failing to restrain rapid tumor progression. In contrast, DMGTF under MW irradiation effectively eliminated tumor cells and suppressed tumor recurrence, enabling the most durable therapeutic benefit. Body weights remained stable throughout the study (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e4\u003c/span\u003eG), suggesting good biocompatibility and tolerability. Tumor-volume curves for individual mice (Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e4\u003c/span\u003eH) further illustrate the growth trajectories, confirming that DMGTF\u0026thinsp;+\u0026thinsp;MW, compared with other groups, not only minimized tumor burden but also extended survival.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e\u003cb\u003ePulmonary Metastasis Inhibition by Microwave-Activated DMGTF\u003c/b\u003e. An H22 pulmonary metastasis model was established to evaluate the in vivo antitumor and survival efficacy of DMGTF (Fig.\u0026nbsp;\u003cspan refid=\"Fig11\" class=\"InternalRef\"\u003e5\u003c/span\u003eA). Upon microwave irradiation, tumor temperatures increased by 25.1\u0026deg;C, 30.5\u0026deg;C, and 33.2\u0026deg;C in the MW, MGTF\u0026thinsp;+\u0026thinsp;MW, and DMGTF\u0026thinsp;+\u0026thinsp;MW groups, respectively (Figs.\u0026nbsp;\u003cspan refid=\"Fig11\" class=\"InternalRef\"\u003e5\u003c/span\u003eB-D), consistent with the subcutaneous tumor results. As shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig11\" class=\"InternalRef\"\u003e5\u003c/span\u003eE and \u003cspan refid=\"Fig11\" class=\"InternalRef\"\u003e5\u003c/span\u003eF, mice were euthanized at different time points in accordance with ethical guidelines when tumor burden reached defined endpoints. Both MGTF\u0026thinsp;+\u0026thinsp;MW and DMGTF\u0026thinsp;+\u0026thinsp;MW treatments effectively suppressed tumor growth and significantly prolonged survival, with all mice in the DMGTF\u0026thinsp;+\u0026thinsp;MW group surviving the full 14 days and exhibiting the smallest tumor volumes. Mice in the Control and Dis groups reached humane endpoints and were euthanized on day 9, whereas the DMGTF and MW-only groups were terminated on day 10 according to ethical requirements. These outcomes reflect the limited antitumor efficacy of Dis or MW alone, which neither eradicated tumors nor prevented recurrence. Similarly, DMGTF and MGTF without MW irradiation showed incomplete degradation and slow therapeutic onset, failing to counteract rapid tumor progression. Individual tumor growth trajectories (Fig.\u0026nbsp;\u003cspan refid=\"Fig11\" class=\"InternalRef\"\u003e5\u003c/span\u003eH) further confirmed that DMGTF\u0026thinsp;+\u0026thinsp;MW not only minimized tumor burden but also extended survival. Notably, while the MW-only group exhibited an initial reduction in tumor volume, rapid regrowth occurred after recurrence, highlighting the potential for tumor relapse following microwave therapy and emphasizing the need for combinatorial strategies to achieve durable treatment outcomes. Take together, these findings demonstrate that DMGTF, upon microwave activation, exhibits potent in vivo antitumor efficacy and markedly prolongs survival in H22-bearing mice. This effect can be attributed to the initial tumoricidal action of microwave irradiation, the dual blockade of tumor lactate metabolism mediated by diclofenac sodium and ROS, and the further cytotoxic contribution from immune cell activation induced by Mg\u0026sup2;⁺.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eAntimetastatic and Immunomodulatory Effects of DMGTF.\u003c/b\u003e As shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig12\" class=\"InternalRef\"\u003e6\u003c/span\u003eA and Figures S7, the control group exhibited the largest number of pulmonary metastatic nodules, which were densely distributed and partially fused into plaques. Both the Dis and DMGTF groups showed reduced metastases to varying degrees; however, slightly larger nodules were observed in the DMGTF group, likely due to the absence of microwave activation that limited nanoplatform performance. In contrast, the MW, MGTF\u0026thinsp;+\u0026thinsp;MW, and particularly the DMGTF\u0026thinsp;+\u0026thinsp;MW groups displayed markedly fewer nodules, with almost no visible lesions in the DMGTF\u0026thinsp;+\u0026thinsp;MW group, confirming that DMGTF effectively mediates microwave-enhanced inhibition of pulmonary metastasis. To further assess immune modulation, tumor and spleen tissues were analyzed by flow cytometry for CD4⁺ and CD8⁺ T-cell populations. As shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig12\" class=\"InternalRef\"\u003e6\u003c/span\u003eB, C and \u003cspan refid=\"Fig12\" class=\"InternalRef\"\u003e6\u003c/span\u003eD, the DMGTF\u0026thinsp;+\u0026thinsp;MW group exhibited the highest proportions of CD4⁺ and CD8⁺ T cells, increasing by up to 1.42- and 1.65-fold relative to the control, respectively. Here, G1-G6 correspond to the Control, MW, Dis, DMGTF, MGTF\u0026thinsp;+\u0026thinsp;MW, and DMGTF\u0026thinsp;+\u0026thinsp;MW groups, respectively.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTaken together, these findings indicate that microwave-activated DMGTF not only suppresses primary tumor growth but also leverages its immune-activating capacity to robustly promote CD8⁺ and CD4⁺ T-cell expansion, thereby transforming immunosuppressive pressure into effective antitumor immune drive and ultimately inhibiting distant pulmonary metastases.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eIn summary, we propose a dual-transformation strategy to address the challenging problem of tumor recurrence and metastasis microwave therapy. In this study, a microwave-and pH-dual-responsive, degradable MOF nanoplatform with liver-cancer-targeting capability has been developed to deliver diclofenac (Dis) and generate ROS for thoroughly disrupting tumor lactic-acid metabolism, transforming lactic acid from a metabolic fuel into metabolic waste. While simultaneously relieving the immunosuppressive TME, the released Mg\u0026sup2;⁺ promotes T-cell proliferation and IFN-λ secretion, thereby reactivating antitumor immunity, inducing long-term immune memory, and converting immune suppression into immune activation. Although the direct regulatory role of Mg\u0026sup2;⁺ on mitochondrial metabolism\u0026ndash;driven T-cell proliferation was not fully delineated in this study, our findings suggest a positive association that warrants further investigation. Future work will focus on clarifying Mg\u0026sup2;⁺-mediated metabolic remodeling in T cells, such as mitochondrial respiration, membrane potential, and ATP production. Comprehensive in vitro and in vivo studies confirmed that the DMGMG nanoplatform not only strategically overcomes the off-target limitations of traditional lactate-metabolism inhibitors, but also effectively suppresses tumor growth and metastasis through this dual strategy. Overall, this work provides a promising approach to resolving tumor recurrence and metastasis after microwave therapy and offers a new paradigm that integrates lactic-acid blockade with immune reactivation for future clinical applications.\u003c/p\u003e"},{"header":"EXPERIMENTAL SECTION","content":"\u003cp\u003e \u003cb\u003eMaterials.\u003c/b\u003e Gallium nitrate (Ga (NO₃) ₃, 99.99%) and polyvinylpyrrolidone (PVP) were purchased from Shanghai Macklin Biochemical Co., Ltd. Magnesium nitrate, terephthalic acid, and ammonia solution were obtained from Sa\u0026rsquo;en Chemical Technology Co., Ltd. N, N-dimethylformamide (DMF, 99.5%) and ethanol (99.7%) were supplied by Beijing Chemical Reagents Company. All reagents were used as received without further purification. Deionized water was used in all aqueous preparations.\u003c/p\u003e \u003cp\u003e\u003cb\u003eAnimals.\u003c/b\u003e All animal experiments were approved by the Experimental Animal Management Committee of the Technical Institute of Physics and Chemistry, Chinese Academy of Sciences (IACUC-IPC-23013) and conducted in accordance with institutional guidelines for the care and use of laboratory animals. Female BALB/c mice (18\u0026thinsp;\u0026plusmn;\u0026thinsp;2 g) were used for all in vivo studies. For establishing the subcutaneous tumor model, H22 hepatocellular carcinoma ascites cells (2 \u0026times; 10⁷) were suspended in 100 \u0026micro;L DMEM and injected into the right axilla of each mouse. Tumor growth was monitored until volumes reached approximately 100 mm\u0026sup3;, at which point in vivo therapeutic or metastasis experiments were initiated.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSynthesis of MgGa-MOF Nanoparticles.\u003c/b\u003e MgGa-MOF nanoparticles were prepared via a solvothermal method. Gallium nitrate (22 mg), magnesium nitrate (7.1 mg), and PVP (100 mg) were dissolved in 10 mL DMF under sonication until a clear solution was obtained. Separately, 54 mg of terephthalic acid was dispersed in 10 mL DMF with ultrasonication. A mixture of 80 mL DMF and 30 \u0026micro;L ammonia solution was prepared, forming a milky suspension. The terephthalic acid solution was slowly added dropwise into the ammonia-containing DMF, during which the suspension gradually became lighter in color. Subsequently, the metal/PVP solution was added dropwise into the mixture, further lightening the suspension. An additional 100 mL of DMF was introduced, and the final solution was stirred thoroughly. The reaction mixture was transferred into a 50 mL Teflon-lined autoclave and heated at 150\u0026deg;C for 10 h. After cooling to room temperature, the precipitates were collected by centrifugation (10,000 rpm, 5 min), washed three times with ethanol to remove residual solvents and unreacted reagents, and dried to yield MgGa-MOF nanoparticles.\u003c/p\u003e \u003cp\u003e \u003cb\u003eSynthesis of Dis @MgGa-MOF and DMGTF Nanoparticles.\u003c/b\u003e For drug loading, MgGa-MOF (10 mg) was dispersed in 2 mL anhydrous ethanol, and diclofenac sodium (20 mg) was added. The mixture was stirred at room temperature for 6 h to allow efficient adsorption of the drug. The resulting Dis@MgGa-MOF nanoparticles were collected by centrifugation, washed three times with ethanol, and dried. To prepare DMGTF, Dis@MgGa-MOF nanoparticles (10 mg) were suspended in 2 mL anhydrous ethanol containing 1-tetradecanol (10 mg L⁻\u0026sup1;) under ultrasonication. Folic acid (1 mg) was dissolved in 3 mL methanol with ultrasonication, and 1 mL of this folic acid solution was added dropwise to the nanoparticle suspension. The mixture was ultrasonicated to ensure uniform coating and interaction. The solvent was removed under vacuum using a rotary evaporator, and the resulting yellowish-white powder was washed with deionized water, centrifuged at 10,000 rpm for 5 min, and collected as DMGTF nanoparticles.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIn Vitro Degradation.\u003c/b\u003e MGTF nanoparticles were dispersed in either saline or PBS (pH 5.7) to simulate physiological and tumor-like microenvironments, respectively. Suspensions were incubated at 37\u0026deg;C with gentle shaking. At predetermined time points (3, 6, and 9 h), nanoparticles were collected by centrifugation for characterization. For microwave-treated samples, additional collections were performed after 10, 20, and 30 min of irradiation. Morphological changes and structural integrity were examined using transmission electron microscopy (TEM) to assess degradation behavior under different conditions.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMicrowave-Responsive Thermal and Catalytic Properties.\u003c/b\u003e Nanoparticle suspensions (0\u0026ndash;15 mg mL⁻\u0026sup1;) in 1 mL saline were transferred to quartz dishes and irradiated at 1.8 W for 5 min. Temperature changes were monitored using an infrared thermal imaging camera at 10 s intervals. To evaluate intracellular ROS generation, four groups were tested: PBS, MW, PBS\u0026thinsp;+\u0026thinsp;MGTF, and PBS\u0026thinsp;+\u0026thinsp;MGTF\u0026thinsp;+\u0026thinsp;MW. Materials were incubated with 1 mg mL⁻\u0026sup1; MGTF for 1 h, and ROS levels were determined using DCFH-DA, with fluorescence intensity measured at 520 nm.\u003c/p\u003e \u003cp\u003e \u003cb\u003eDrug Release Study.\u003c/b\u003e Dis release from DMGTF nanoparticles (5 mg mL⁻\u0026sup1;) was investigated under three conditions: PBS pH 7.4, PBS pH 5.7, and PBS pH 5.7 with microwave irradiation (1.8 W, 5 min). Samples were incubated at 37\u0026deg;C in a shaking water bath. At 1, 3, 6, and 12 h, supernatants were collected after centrifugation and analyzed using UV-vis spectrophotometry at 276 nm. Cumulative drug release was calculated based on a standard calibration curve.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIn Vitro Cytotoxicity.\u003c/b\u003e L929, HepG2, and H22 cells were seeded in 96-well plates and treated with MGTF nanoparticles at concentrations of 0-200 \u0026micro;gmL⁻\u0026sup1; for 24 h. Subsequently, 20\u0026micro;L of MTT solution was added, and cells were incubated for 4 h. The supernatant was removed, and 150\u0026micro;L DMSO was added to dissolve formazan crystals. Absorbance was measured using a microplate reader, and cell viability was calculated relative to untreated controls.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIn Vitro Therapeutic Evaluation.\u003c/b\u003e HepG2 and H22 cells were treated with seven groups (Control, MW, Dis, MGTF, MGTF\u0026thinsp;+\u0026thinsp;MW, DMGTF, DMGTF\u0026thinsp;+\u0026thinsp;MW) at 100\u0026micro;gmL⁻\u0026sup1; for 24 h. Microwave groups were irradiated for 5 min and then reseeded into 96-well plates, while untreated groups were directly reseeded. Cell viability was assessed after 24 h using MTT and CCK-8 assays, measuring absorbance to evaluate the therapeutic effects of DMGTF with or without MW treatment.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCellular Internalization and Targeting.\u003c/b\u003e For internalization studies, MGTF nanoparticles were labeled with rhodamine and incubated with HepG2 cells (100\u0026micro;g mL⁻\u0026sup1;) for 3, 6, 9, and 12 h. Uptake was visualized using confocal laser scanning microscopy (CLSM). The targeting ability of DMGTF was evaluated by hyperspectral imaging. DMGT or DMGTF (1 mg/mL, 1\u0026micro;L) was deposited on glass coverslips and sealed to build spectral libraries using a Cytoviva push-broom system. HepG2 cells were seeded onto the coverslips and incubated with 100\u0026micro;g mL⁻\u0026sup1; nanoparticles for 6 h, washed, fixed with 4% neutral formaldehyde, and imaged to assess folate-mediated cellular uptake.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMCT4 Inhibition and Lactate/Extracellular pH Assays.\u003c/b\u003e HepG2 cells were treated with 100\u0026micro;g mL⁻\u0026sup1; of control, MW, Dis, DMGTF or MGTF\u0026thinsp;+\u0026thinsp;MW, DMGTF\u0026thinsp;+\u0026thinsp;MW for 6 h. Cells were fixed in pre-chilled ethanol, permeabilized with 0.2% Triton X-100, blocked with 1% BSA for 1 h, and incubated with CL488-22787 primary antibody (1:200) for 1.5 h at room temperature. Fluorescence imaging was used to evaluate MCT4 expression. For lactate secretion, cells were treated similarly, and extracellular lactate was measured using a commercial assay kit. Extracellular pH of the medium was also recorded to assess the effect of DMGTF on TME acidity.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIntracellular ROS and Mitochondrial Damage.\u003c/b\u003e Cells were treated with formulations (100\u0026micro;g mL⁻\u0026sup1;) for 6 h, and H₂O₂ (100\u0026micro;M) was used as a positive control. MW groups were irradiated for 5 min. ROS generation was measured using DCFH-DA, and mitochondrial membrane potential was assessed with 10\u0026micro;M JC-1 probe. Cells were washed and imaged under fluorescence microscopy to visualize mitochondrial integrity and oxidative stress.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCo-Culture with Immune Cells.\u003c/b\u003e HepG2 cells were cultured alone or with CTLL-2 immune cells and treated with formulations as previously described. Scratch assays were performed at the time of treatment, and wound closure was observed after 48 h using fluorescence microscopy. CTLL-2 cells were analyzed by flow cytometry to quantify cell number and expression of IFN-γ and CD69, evaluating immune activation induced by DMGTF treatments.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIn Vivo Therapeutic Evaluation.\u003c/b\u003e Tumor-bearing mice (~\u0026thinsp;100 mm\u0026sup3;) were randomly assigned to six groups (control, MW, Dis, DMGTF, MGTF\u0026thinsp;+\u0026thinsp;MW, DMGTF\u0026thinsp;+\u0026thinsp;MW). Nanoparticles (100 mg\u0026middot;kg⁻\u0026sup1;) were administered intravenously. MW-treated groups received irradiation 6 h post-injection. Tumor volumes and body weights were monitored every day. At study endpoint, tumors and major organs were collected for histological analysis to evaluate treatment efficacy and biocompatibility.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eS.Y., and X.M. conceived the idea and supervised the research. Y.L. and Y.W. wrote and revised the manuscript. S.M. and F.L. helped check the data and provided valuable advice. All authors have approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing financial interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll animal experiments have got permissions from the Institutional Animal Care and Use Committee (IACUC) guidelines of the Technical Institute of Physics and Chemistry (IPC) Animal Care (NO.\u0026nbsp;IACUC-IPC-2506-011).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (82172048, U21A20378), the Science and Education Cultivation Fund of the National Cancer and Regional Medical Center of Shanxi Provincial Cancer Hospital (TD2023003, BD2023004, QH2023013), the Science and Technology Cooperation and Exchange Special Project of Shanxi Province (202304041101030, 202304041101002), the Shanxi Center of Technology Innovation for Controlled and Sustained Release of Nano-drugs (202104010911026). Fundamental Research Program of Shanxi Province (202403021221305).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data are available in the main text, supporting information, and are also on request from the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLlovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS. Hepatocellular Carcinoma. Nat Rev Dis Primers. 2021;7(1):6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41572-020-00240-3\u003c/span\u003e\u003cspan address=\"10.1038/s41572-020-00240-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGravitz L, Liver Cancer. 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Small. 2024;20(17):e2308055. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/smll.202308055\u003c/span\u003e\u003cspan address=\"10.1002/smll.202308055\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-nanobiotechnology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jnan","sideBox":"Learn more about [Journal of Nanobiotechnology](http://jnanobiotechnology.biomedcentral.com)","snPcode":"12951","submissionUrl":"https://submission.nature.com/new-submission/12951/3","title":"Journal of Nanobiotechnology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Microwave therapy, Microwave-responsive materials, Immune metabolism, Lactate metabolism modulation, Immune reactivation, Magnesium ions (Mg²⁺), Hepatocellular carcinoma","lastPublishedDoi":"10.21203/rs.3.rs-8600293/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8600293/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMicrowave ablation (MWA) has emerged as one of the preferred modalities for treating hepatocellular carcinoma (HCC). However, its therapeutic efficiency is restricted by lactate accumulation after MWA. Lactate serves as a metabolic fuel for residual tumor cells, as well as acidifies the tumor microenvironment (TME) and impairs immune function, thereby fostering tumor recurrence and metastatic dissemination. Herein, we designed a dual-transformation strategy that turns metabolic fuel into waste and immunosuppressive pressure into power, implemented via bimetallic MOF-based nanoplatform (Dis@MgGa-MOF@TD/FA, DMGTF NCs), to counteract microwave-induced lactate elevation, reactivate immune activity and suppress primary tumor growth and metastatic progression. Specifically, after intravenous administration, folic acid (FA)-modified DMGTF accumulates in HCC, where microwave irradiation opens the 1-Tetradecanol (TD) gate to release diclofenac sodium (Dis). The released Dis suppresses MCT4-mediated lactate efflux, thereby disrupting lactate-driven energy supply and reshaping the TME. Meanwhile, microwave-activated DMGTF generates abundant ROS to impair mitochondrial lactate oxidation and collectively transforms metabolic \"fuel\" into biologically inert \"waste\". Moreover, framework-derived Mg\u0026sup2;⁺ restarts T cells, boosts proliferation, and augments IFN-γ secretion, converting immunosuppressive \"pressure\" into antitumor \"power\". As a result, DMGTF NCs combined with MW achieve excellent therapeutic effects in a model of hepatocellular carcinoma and lung metastasis. This MOF-based dual-transformation strategy provides a promising solution to the long-standing challenge of post-MWA tumor relapse and dissemination, offering new insights into the effective control of liver cancer.\u003c/p\u003e","manuscriptTitle":"A Dual-Transformable MgGa-MOF Nanoplatform for HCC Therapy via Lactate Metabolism Blockade and Immune Reactivation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-29 17:13:53","doi":"10.21203/rs.3.rs-8600293/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-30T18:43:14+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-29T07:54:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"51164783642798538551626692391591517622","date":"2026-01-29T05:07:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-29T02:38:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"168256688908669376790879012738294408287","date":"2026-01-27T01:37:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"231659575200457751042234284980535516000","date":"2026-01-27T01:36:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-26T16:32:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-21T09:12:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-21T09:12:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Nanobiotechnology","date":"2026-01-14T09:40:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-nanobiotechnology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jnan","sideBox":"Learn more about [Journal of Nanobiotechnology](http://jnanobiotechnology.biomedcentral.com)","snPcode":"12951","submissionUrl":"https://submission.nature.com/new-submission/12951/3","title":"Journal of Nanobiotechnology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ea6f6d81-be43-4627-9626-6110ef32b433","owner":[],"postedDate":"January 29th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-07T16:03:29+00:00","versionOfRecord":{"articleIdentity":"rs-8600293","link":"https://doi.org/10.1186/s12951-026-04356-8","journal":{"identity":"journal-of-nanobiotechnology","isVorOnly":false,"title":"Journal of Nanobiotechnology"},"publishedOn":"2026-04-05 15:59:55","publishedOnDateReadable":"April 5th, 2026"},"versionCreatedAt":"2026-01-29 17:13:53","video":"","vorDoi":"10.1186/s12951-026-04356-8","vorDoiUrl":"https://doi.org/10.1186/s12951-026-04356-8","workflowStages":[]},"version":"v1","identity":"rs-8600293","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8600293","identity":"rs-8600293","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}