Jul 2026· Journal of Controlled Release· pp.
115156
· 0 citations· 60 references
Medicine
TL;DR
A metabolism-oriented therapeutic approach to overcome tumor metabolic adaptability and enhance antitumor efficacy is developed that integrates dual metabolic intervention with photodynamic therapy (PDT) to induce metabolic collapse.
Abstract
Tumor cells exhibit pronounced metabolic plasticity, enabling adaptive compensation among metabolic pathways to sustain malignant growth and therapeutic resistance. To address this challenge, we develop a glutathione (GSH)-responsive peptide-based nanocomplex (siMCT4/CSE) that integrates dual metabolic intervention with photodynamic therapy (PDT) to induce metabolic collapse. The nanoplatform is constructed via the co-assembly of a disulfide-containing amphiphilic peptide and DSPE-PEG2k-FA, enabling the co-delivery of siRNA targeting monocarboxylate transporter 4 (siMCT4), the fatty acid β-oxidation (FAO) inhibitor Etomoxir, and chlorin e6 (Ce6). Following cellular internalization, elevated intracellular GSH triggers nanocomplex disassembly and synchronized release of therapeutic components. Mechanistically, siMCT4 inhibits lactate efflux, leading to intracellular lactate accumulation and feedback suppression of glycolysis, thereby limiting energy production, while Etomoxir blocks FAO by inhibiting carnitine palmitoyltransferase 1 (CPT1), restricting alternative energy supply. Under these metabolically constrained conditions, Ce6-mediated PDT generates reactive oxygen species (ROS), aggravating oxidative damage and amplifying metabolic stress. In 4 T1 tumor-bearing mice, this combined disruption of lactate efflux and FAO, together with PDT, drove tumor cells into severe metabolic imbalance, leading to significant tumor growth inhibition. Collectively, this strategy provides a metabolism-oriented therapeutic approach to overcome tumor metabolic adaptability and enhance antitumor efficacy.
Tumor cells exhibit a hyper-glycolytic phenotype, resulting in massive lactic acid (LA) production that acidifies the tumor microenvironment (TME) and fosters immunosuppression. Current lactate-targeted therapies often lack synergistic dual-directional regulation. Herein, we engineer an exosomal nanoplatform, PpIX/siRNA@EXO-LOD, to simultaneously disrupt intra- and extracellular LA homeostasis, thereby enabling synergistic metabolic and photodynamic therapy (PDT). The system integrates three key components: protoporphyrin IX (PpIX) for PDT, siRNA targeting monocarboxylate transporter 4 (MCT4) for intracellular metabolic interference, and surface-displayed lactate oxidase (LOD) for extracellular catalytic starvation. Upon epithelial cell adhesion molecule (EpCAM)-mediated targeting, the nanovesicle triggers a cascade of synergistic effects. Crucially, siRNA-mediated silencing of MCT4 induces lethal intracellular acidosis, leading to significant intracellular H2O2 accumulation. This elevated H2O2 level acts as a booster for PpIX-generated reactive oxygen species (ROS) upon laser irradiation, creating an amplified oxidative stress burst that overwhelms tumor cell defenses. Concurrently, surface-anchored LOD consumes extracellular LA, alleviates lactate-induced immunosuppression. In vivo studies demonstrate that this dual-regulation strategy effectively inhibits tumor growth, downregulates metastasis-related factors (amphiregulin (AREG), ATP-binding cassette sub-family B member 1 (ABCB1)), and reprograms the TME from an immunosuppressive state to an immunologically active state. This work presents a precision nanomedicine strategy that leverages the interplay between metabolic modulation and photodynamic amplification for enhanced cancer treatment.
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A TME-responsive nanoplatform composed of MPDA core shielded by manganese dioxide (MnO2) shell, enabling sequential co-delivery of doxorubicin and resveratrol for chemo-/chemodynamic/photothermal therapy, offering a promising paradigm for overcoming chemoresistance in bladder cancer.
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In vitro and in vivo evaluations confirm that R-A/G@Z effectively suppresses aggressive breast tumors while maintaining a good safety profile, offering a promising strategy for intelligent metabolic-chemodynamic cancer nanomedicine.
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It is proposed that PTT interferes with tumor metabolism through organelle stress and synergizes with exogenous drugs to enhance metabolic perturbation, thereby eliciting a potent antitumor immune response.
Lin Chen, Hanyu Zhang, Yunlong Wang et al.· Frontiers in Immunology· 0 citations
Metal-nanozyme-mediated chemodynamic therapy (CDT) has emerged as a promising strategy for the treatment of deep-seated tumors; however, its therapeutic efficacy is often limited by insufficient reactive oxygen species (ROS) generation and poor spatiotemporal control of enzyme-like activity within the tumor microenvironment (TME). Here, we report a biomimetic nanoplatform, CuO@MSN/TH302@GOx@CM (CMTGM), which integrates a programmed multi-enzyme cascade consisting of a copper oxide (CuO) core, a dendritic mesoporous silica (MSN) intermediate shell, the hypoxia-activated prodrug TH302, and surface-conjugated glucose oxidase (GOx). This hierarchical architecture enables stepwise activation and release of distinct enzyme-mimetic functions. Furthermore, CMTGM is cloaked with a homologous tumor cell membrane to enhance tumor-targeting capability. Following internalization of CMTGM into the tumor cells, GOx catalyzes glucose oxidation to generate H2O2 and gluconic acid, thereby disrupting tumor metabolism and acidifying the microenvironment, which accelerates MSN degradation and promotes the release of Evofosfamide (TH302) while exposing the CuO core. The Cu2+ ions released from the core exert glutathione peroxidase-like activity, depleting intracellular glutathione, and peroxidase-like activity, converting H2O2 into highly cytotoxic hydroxyl radicals, thereby amplifying CDT. Meanwhile, GOx-mediated oxygen consumption aggravates hypoxia and activates TH302, which further enhances therapeutic efficacy. This spatiotemporally programmed cascade involving substrate self-supply, responsive degradation, catalytic amplification, and prodrug activation eventually triggers multiple programmed cell death pathways and enhances immunogenic cell death, ultimately eliciting systemic anti-tumor immunity. In both in vitro and in vivo studies, CMTGM demonstrated efficient tumor targeting, robust tumor suppression, and favorable biosafety of in a 4 T1 breast cancer model. This study provides a generalizable strategy for the rational design of programmable catalytic nanomedicines with integrated multifunctionality.
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