Metabolic regulation-driven nanoparticles for tumor vulnerabilization and enhanced photodynamic therapy.

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.