Aug 2026· Journal of Advanced Research· 0 citations· 43 references
Medicine
TL;DR
BIMLM is developed as a biomimetic nanoplatform integrating lactate oxidase (LOX)-driven lactate exhaustion with MnO2-coated IR-780 for TME remodeling and self-amplifying ROS generation that enhances PDT/CDT efficacy while triggering metabolic starvation and ferroptosis, which collectively enable tumor eradication.
Abstract
INTRODUCTION
Strategic harnessing and modulation of the tumor microenvironment (TME) can overcome its inherent therapeutic barriers and enhance treatment efficacy. TME hallmarks, including hypoxia, excessive glutathione (GSH), and insufficient H2O2, severely limit reactive oxygen species (ROS)-based therapies.
Methods
To address this issue, leveraging the high lactate level in TME, we developed BIMLM (BSA-IR780-MnO2@LOX@Membrane) as a biomimetic nanoplatform integrating lactate oxidase (LOX)-driven lactate exhaustion with MnO2-coated IR-780 for TME remodeling and self-amplifying ROS generation. BIMLM was fabricated by first preparing MnO2-coated IR-780 nanoparticles, then immobilizing LOX, and finally cloaking them with tumor cell membranes. After BIMLM accumulates selectively within tumor tissue, intratumoral excess lactate triggers the sequential therapeutic cascades. Specifically, LOX-catalyzed lactate oxidation generates H2O2 to induce metabolic starvation by disrupting energy supply. This H2O2 is then decomposed by MnO2 to produce O2, which simultaneously facilitates cyclic lactate oxidation and enhances photodynamic therapy (PDT). The resulting Mn2+ further triggers a Fenton-like reaction, converting the self-supplied H2O2 into •OH and thereby amplifying chemodynamic therapy (CDT). Concurrently, GSH depletion increases cellular susceptibility to ROS, further potentiating both PDT and CDT. Notably, coordinated GSH downregulation and ROS upregulation synergistically trigger ferroptosis, which combines with apoptosis to achieve potent tumor suppression.
Results
Taken together, the nanoplatform reconfigures the TME through lactate depletion, H2O2 elevation, hypoxia alleviation, and GSH scavenging. This series of changes creates a self-amplifying cycle that enhances PDT/CDT efficacy while triggering metabolic starvation and ferroptosis, which collectively enable tumor eradication. This strategy establishes a promising paradigm for high-efficiency tumor therapy.
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Nianting Xiao, Xiao He, Daxiu Li et al.· Journal of Colloid and Inter...· 0 citations
This study provides a generalizable strategy for the rational design of programmable catalytic nanomedicines with integrated multifunctionality, and demonstrates efficient tumor targeting, robust tumor suppression, and favorable biosafety of in a 4 T1 breast cancer model.
Beibei Sun, R. Wan, Runwei Wang et al.· Journal of Colloid and Inter...· 0 citations
Conventional reactive oxygen species (ROS)-mediated tumor therapies such as photo-, sono-, and chemodynamic therapies are often limited by inadequate penetration depth of external stimuli and insufficient endogenous ROS substrates (e.g., O₂ and H₂O₂). Here, we report that horseradish peroxidase (HRP) can catalyze artemisinin to generate ROS. Based on this, a "ROS bomb" nanomedicine was designed for antitumor immunotherapy. The nanocarrier consists of silica cross-linked micelles incorporating ROS-cleavable thioketal bonds and encapsulated artemisinin as the payload, with surface-immobilized HRP serving as the trigger. Within the tumor microenvironment with elevated H₂O₂, the thioketal linkers are cleaved to release artemisinin, initiating an HRP-catalyzed ROS cascade. The ROS burst induces immunogenic cell death and activates the STING pathway in dendritic cells assisted by the co-released drug SN38, effectively suppressing the growth of immunosuppressive triple-negative breast tumors. This exogenous ROS delivery strategy overcomes the restrictions of conventional ROS therapies, offering a potent approach for treating deep-seated tumors.
Keqiang Lu, Yaoquan Su, Xingchen Zhou et al.· Journal of Controlled Releas...· 0 citations
A biodegradable biomimetic nanoplatform (HMCDL@TK-M) was constructed by combining hydrogen-doped HxMoO3 nanoparticles, dual-drug loading, and a hybrid spinach-cancer cell membrane coating. The system features pH-responsive biodegradability, tumor-homing capability, and high NIR-II photothermal conversion. An oxygen-lactate cascade, formed via thylakoid membrane-mediated H2O2 decomposition and lactate oxidase-driven lactate oxidation, alleviates hypoxia and depletes lactate in the tumor microenvironment. This dual metabolic modulation reprograms M2 macrophages to M1, promotes dendritic cell maturation, and reduces Treg infiltration. In 4T1 tumor-bearing mice, HMCDL@TK-M achieves strong tumor accumulation, effective photothermal ablation, and combined with lactate depletion, complete tumor eradication without systemic toxicity. The treatment also induces robust CD4+/CD8+ effector memory T-cell responses, providing durable antitumor immunity. This work demonstrates a synergistic metabolic-photothermal immunotherapy strategy for efficient and long-lasting cancer treatment.
Shuo Gao, Yu Chen, Yan-Xi He et al.· Advanced Healthcare Material...· 0 citations
The results indicate that calcium overload, FTY720-mediated TRPM7 inhibition, and MnO2-induced redox imbalance can drive PANoptosis, offering a new concept for enhancing cancer immunotherapy.
Aiyang Tong, Yang Zhou, Yang Ding et al.· Materials Today Bio· 0 citations
Tumor hypoxia diminishes antitumor immunity by stabilizing HIF-1α, promoting M2-like macrophage polarization, and impairing cytotoxic T-cell activity. To reverse these effects, we developed hemoglobin-loaded biomimetic nanoparticles (Hb-BNPs) using a modified nanoprecipitation strategy. The nanoparticles encapsulate hemoglobin within a polycaprolactone matrix and are cloaked with RBC/A549 membranes to provide immune camouflage and sustained oxygen release. This study evaluates their ability to reoxygenate the tumor microenvironment and restores immune and therapeutic responses in non-small-cell lung carcinoma (NSCLC).
Hb-BNPs were synthesized via modified nanoprecipitation and membrane cloaking. Physicochemical features were assessed by DLS, TEM. Hypoxia was induced in A549 cells, followed by Hb-BNP treatment. qRT-PCR, paclitaxel IC50 assays, 3D spheroids, LunX CAR-T cytotoxicity, and KANK1-transfection studies evaluated immunologic and therapeutic responses (all n = 3, ANOVA/t).
Under hypoxia, HIF1A, VEGF, BNIP3, ENO1, HK1, PGK1 were upregulated by 5—8-fold (p < 0.01). After Hb-BNP reoxygenation, these genes were downregulated by 4—6-fold (p < 0.001), and dissolved oxygen increased 5.3-fold (p < 0.001). Oxygen recovery improved the immune function as LunX CAR-T cytotoxicity increased 2.3-fold (p < 0.01), and KANK1-driven transgene expression increased 2.7-fold (p < 0.05). Co-treatment with paclitaxel reduced IC50 from 25,612 ng/mL to 781 ng/mL (p < 0.0001) and enhanced 3D spheroid core cell death 2.4-fold (p < 0.01). Hb-BNPs did not elevate IL-6, TNF-α, or IL-8 in THP-1 macrophages, confirming immune tolerance.
Hb-BNPs reoxygenate hypoxic tumors, suppress HIF-1α signaling, and restore cytotoxic immune function without inducing inflammation. By normalizing oxygen balance, these biomimetic nanoparticles enhance CAR-T activity, gene transfection, and chemotherapy response, offering a scalable, immune-tolerant platform to overcome hypoxia-driven resistance in solid tumors.
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Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
H.A. Gandhi, Jaydeep Bhattacharya· Journal of Immunology· 0 citations
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