文献类型：期刊文献

英文题名：Peptide Hydrogels for Renal Carcinoma Therapy via Synergistic Inhibition of Glycolysis and Mitochondrial Metabolism Reprogramming

作者：Ge, Zhenghong[1];Xu, Jiaxi[1];Meng, Fanying[1];Sun, Min[2,3];He, Le[2,3];Fan, Zhen[1];Du, Jianzhong[1,2,3]

机构：[1]Tongji Univ, Sch Mat Sci & Engn, Dept Polymer Mat, Shanghai 201804, Peoples R China;[2]East China Univ Sci & Technol, Sch Mat Sci & Engn, Shanghai 200237, Peoples R China;[3]Tongji Univ, Shanghai Peoples Hosp 4, Translat Res Inst Brain & Brain Like Intelligence, Sch Med,Clin Res Ctr Anesthesiol & Perioperat Med, Shanghai 200434, Peoples R China

年份：2025

卷号：17

期号：25

起止页码：36487

外文期刊名：ACS APPLIED MATERIALS & INTERFACES

收录：;EI(收录号：20252518640425);WOS:【SCI-EXPANDED(收录号:WOS:001510253800001)】；

基金：This research was supported by National Natural Science Foundation of China (52222306, 22335005, 22475154 and 22305177), Shanghai international scientific collaboration fund (23520710900), Shanghai Rising-Star Program (Sailing, 23YF1433000), and Natural Science Foundation of Shanghai (20ZR1443200), the Fundamental Research Funds for the Central Universities. Dr. Erik Jan Cornel (Ph.D. in Chemistry, University of Sheffield, United Kingdom) helped to review and revise the entire manuscript.

语种：英文

外文关键词：peptide; hydrogels; oraldelivery; metabolism programming; glycolysis

摘要：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. In vitro 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. In vivo 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.