Smart Metabolism Nanovalve Reprograms Cancer Energy Homeostasis for Maximizing Photometabolism Therapy

Better understanding of important roles of metabolic reprogramming in therapeutic resistance provides insights into advancing cancer treatment. Herein, we present a photoactive metabolic reprogramming strategy (termed as photometabolism therapy, PMT), in which photoregulation of mitochondria leads to cancer cell metabolic crisis, and consequently overcomes therapeutic resistance while improving treatment efficacy. In specific, a stimuli-responsive metabolism NanoValve is developed for improving cascade cancer therapy through blocking mitochondrial energy supply. NanoValve is composed of an onion-like architecture with a gold nanorod core, a mesoporous silica shell encapsulating photosensitizer chlorin e6 and oxygen-saturated perfluorocarbon, and cationic liposomal coating with MMP2-cleavable polyethylene glycol corona, which together initiate mitochondria-specific PMT. NanoValve selectively responds to tumor-overexpressed MMP2 and achieves size decrease and charge reversal, which consequently enhances tumor penetration, cancer cell uptake, endosome escape, and most critically, mitochondrial accumulation. Importantly, NanoValve-mediated phototherapy can strongly destruct mitochondrial energy metabolism, thereby minimizing therapy resistance. Particularly, perfluorocarbon supplies oxygen to further overcome the tumor hypoxia-associated therapeutic barrier and maximizes synergistic anticancer effects. In vivo studies show that NanoValve can effectively eliminate tumors without side effects, thereby dramatically prolonging the survival of tumor-bearing mice. Thus, NanoValve provides a modular PMT approach and has the potential of advancing the treatment of malignancy.