Intracellular Glutathione Cleaved Long-Targeting Chains of Cancer Cells and Macrophages to Exposedly Activate Mitochondria Delivery of Liposomes for Enhancing Antitumor Efficacy by Metabolic Reprogramming

Considering that M2-tumor associated macrophages (TAMs) performing immunosuppressive function in tumor microenvironment (TME) rely on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) metabolic pathways for energy supply, whereas M1 TAMs with antitumor effect and cancer cells mainly rely on glycolysis as energy source, so targeting the vital subcellular organelles of mitochondria for metabolic reprogramming of TAMs and cancer cells by nanocarriers could be expected as promising approaches for enhancing antitumor efficacy. Herein, two kinds of liposomes with M2 TAMs/mitochondria-targeting co-delivered the OXPHOS inhibitor atractyloside (ATR) and curcumin (CUR) for lipid intervention (MST@A/C), and tumor/mitochondria-targeting liposomes encapsulated 2-DG (BST@2-DG) were fabricated. MST@A/C located in mitochondria of M2 TAMs could inhibit OXPHOS and lipid uptake by downregulating CD36 expression, killing M2 TAMs and induced the transformation of M2 to M1 TAMs. Simultaneously, BST@2-DG located in mitochondria of 4T1 cells inhibited glycolysis and offered additional glucose for repolarization of M2 into M1 TAMs, which further improved antitumor efficacy both in vitro and in vivo. The GSH-activated mitochondria-targeting composited liposomes through triple-cellular metabolism disruption provide a novel method for advancement of antitumor.