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.
Si-Si Zhou, Yu Cao, Xian-Biao Wang et al.· Advanced Healthcare Material...· 0 citations
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.
Boye Zhang, Yuli Chen, Pengyan Qiao et al.· Journal of Advanced Research· 0 citations
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.
Zhihua Zeng, Chao Hu, Yihe Li et al.· Colloids and Surfaces B: Bio...· 0 citations
Breast cancer presents a formidable global health challenge, with traditional monotherapies frequently hampered by limited specificity and off-target toxicity. Herein, we developed a highly integrated, biomimetic, and pH-responsive zeolitic imidazolate framework-8 (ZIF-8) nanoplatform, RBCm-coated nanoparticles (R-A/G@Z), tailored for cascaded starvation and potentiated ferroptosis therapy. Through a one-pot biomineralization approach, the hydrophobic ferroptosis inducer artesunate (ART) and the hydrophilic metabolic enzyme glucose oxidase (GOx) were co-encapsulated within a ZIF-8 framework, followed by red blood cell membrane (RBCm) surface cloaking. The R-A/G@Z platform demonstrates enhanced tumor accumulation and undergoes acid-triggered disassembly within the tumor microenvironment (TME). Upon internalization, GOx-mediated glucose oxidation serves to starve the tumor of its primary energy source while continuously generating hydrogen peroxide (H2O2) and protons. This localized acidification accelerates structural degradation, supplying ample H2O2 to fuel an ART-triggered Fenton-like reaction. Crucially, the concurrent liberation of Zn2+ from the ZIF-8 lattice orchestrates a dual-regulatory axis: it downregulates ferroportin 1 (FPN1) to retain reactive iron intracellularly, and upregulates tumor protein p53 (p53) to suppress the solute carrier family 7 member 11-glutathione-glutathione peroxidase 4 (SLC7A11-GSH-GPX4) antioxidant shield. This integrated strategy overcomes the tumor's redox defenses, leading to ferroptotic cell death. 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.
Nianting Xiao, Xiao He, Daxiu Li et al.· Journal of Colloid and Inter...· 0 citations
Metabolic reprogramming is a hallmark of malignant tumors, providing tumor cells with energy and promoting immune escape through changes in glucose, lipid, and amino acid metabolism. Photothermal therapy (PTT) not only eliminates tumor cells through localized hyperthermia but also disrupts metabolic networks. However, the mechanisms by which PTT-induced metabolic perturbation engages antitumor immunity remain a considerable challenge. This review proposes 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. We first detail how hyperthermia and ROS induced by PTT damage organelles, leading to organelle stress, including mitochondrial depolarization, endoplasmic reticulum (ER) proteotoxicity, cytosolic enzyme denaturation, and nucleolar stress. Critically, stressed organelles release immunogenic signals, activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to trigger innate immune recognition, and regulating the functions of CD8+ T cells and macrophages through metabolites in the tumor microenvironment (TME). We also discuss how tumor cells activate adaptive responses, such as heat shock protein (HSP) upregulation and metabolic switching, to resist sublethal thermal stress, and evaluate synergistic strategies designed to amplify organelle stress and overcome thermotolerance. Finally, we focus on the latest advancements in overcoming tumor heterogeneity and advancing the clinical translation of targeted organelle PTT nanoplatforms. It is expected to elucidate the mechanism by which organelle stress in PTT causes metabolic perturbation, the tumor adaptive response, and its impact on tumor immunity, providing innovative ideas and references for the development of metabolic and tumor combined treatment strategies based on PTT.
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.
Beibei Sun, R. Wan, Runwei Wang et al.· Journal of Colloid and Inter...· 0 citations