Peptide-based nanocomplex (siMCT4/CSE) induces metabolic collapse in 4T1 tumors, enhancing photodynamic therapy

Tumor cells exhibit remarkable metabolic plasticity, allowing them to adapt and resist therapies by compensating among various metabolic pathways. This adaptability is a major challenge in cancer treatment, as it enables malignant growth and therapeutic resistance. Current standard-of-care often fails to fully address this metabolic resilience, leading to suboptimal outcomes. Targeting key metabolic vulnerabilities, such as lactate efflux via MCT4 and fatty acid β-oxidation (FAO), represents a promising strategy to overcome this resistance and enhance the efficacy of established treatments like photodynamic therapy (PDT).

Researchers developed a glutathione (GSH)-responsive peptide-based nanocomplex (siMCT4/CSE), constructed via the co-assembly of a disulfide-containing amphiphilic peptide and DSPE-PEG2k-FA. This nanoplatform was designed for the co-delivery of siRNA targeting monocarboxylate transporter 4 (siMCT4), the fatty acid β-oxidation (FAO) inhibitor Etomoxir, and chlorin e6 (Ce6). The nanocomplex's therapeutic efficacy was evaluated in 4T1 tumor-bearing mice. Following cellular internalization, elevated intracellular GSH was designed to trigger nanocomplex disassembly and synchronized release of its therapeutic components, aiming to induce metabolic collapse and enhance PDT outcomes.

The siMCT4/CSE nanocomplex successfully induced a severe metabolic imbalance in 4T1 tumor cells. Mechanistically, siMCT4 effectively inhibited lactate efflux, leading to a detrimental accumulation of intracellular lactate. This accumulation, in turn, caused feedback suppression of glycolysis, significantly limiting the tumor cells' primary energy production pathway. Concurrently, Etomoxir blocked fatty acid β-oxidation (FAO) by inhibiting carnitine palmitoyltransferase 1 (CPT1), thereby restricting an essential alternative energy supply. Under these metabolically constrained conditions, Ce6-mediated photodynamic therapy (PDT) generated reactive oxygen species (ROS), which aggravated oxidative damage and amplified the existing metabolic stress. The combined disruption of lactate efflux and FAO, synergized with PDT, drove tumor cells into a state of severe metabolic imbalance. This multi-pronged approach led to: > Significant tumor growth inhibition in 4T1 tumor-bearing mice, demonstrating the strategy's efficacy in overcoming tumor metabolic adaptability and enhancing antitumor effects.