Peptide Hydrogels for Renal Carcinoma Therapy via Synergistic Inhibition of Glycolysis and Mitochondrial Metabolism Reprogramming

The pathogenesis of renal cell carcinoma (RCC) is intricately associated with metabolic reprogramming as a key characteristic of cancer malignancy. This study presents a peptide-based hydrogel platform to disrupt tumor metabolic plasticity by simultaneously targeting oxidative phosphorylation (OXPHOS) and glycolysis. The hydrogels were synthesized through the self-assembly of 9-fluorenylmethoxycarbonyl-modified diphenylalanine (Fmoc-FF), followed by electrostatic complexation with glycol chitosan (GCS). The hydrophobic OXPHOS inhibitor Oligomycin A (Oligo) and the hydrophilic glycolysis inhibitor 2-deoxy-d-glucose (2-DG) were efficiently co-loaded into the peptide hydrogels. <i>In vitro</i> studies revealed that monotherapy with either Oligo or 2-DG is limited by compensatory metabolic rewiring as tumor cells switch between glycolysis and OXPHOS to maintain energy homeostasis. In contrast, dual inhibition induced synthetic lethality, disrupting cellular energy homeostasis and activating apoptotic pathways. Our findings validate the potential of integrating mitochondrial bioenergetic disruption with glycolytic inhibition in a single and orally administered delivery system. <i>In vivo</i> evaluation in RCC xenografts demonstrated that oral hydrogel codelivery of Oligo and 2-DG achieved potent tumor suppression with minimal systemic toxicity. By integrating tumor-selective delivery, dual metabolic targeting, and oral administration, this work presents a transformative strategy to address metabolic heterogeneity and clinical toxicity, offering a versatile platform for precision cancer therapy.