An Energy Metabolism Nanoblocker for Cutting Tumor Cell Respiration and Inhibiting Mitochondrial Hijacking from Cytotoxic T Lymphocyte

Abstract Energy metabolism modulation emerges as a highly regarded strategy for tumor therapy. However, the efficacy of targeting energy metabolism in tumor cells remains unsatisfactory due to the alternate energy production pathways by switching between mitochondrial respiration and glycolysis. In addition, tumor cells can hijack mitochondria from peripheral immune cells to maintain their energy metabolism as an extra respiratory pathway. In this study, a CD44 receptor‐targeted hyaluronic acid energy metabolism nanoblocker is developed to achieve bidirectional blockade of basal respiration in tumor cells with the loaded mitochondrial oxidative phosphorylation (OXPHOS) inhibitor nebivolol hydrochloride, and the glycolysis inhibitor 3‐bromopyruvate. Furthermore, combined intraperitoneal injection of L‐778123 hydrochloride inhibits mitochondrial transfer, thus blocking the extra respiratory pathway of tumor cells and the depletion of cytotoxic T lymphocytes. This emerging strategy, which involves depleting tumor cell energy through inhibition of basal respiration (OXPHOS/glycolysis) and extra respiration, while synergistically enhancing effector immune cells to maintain systemic anti‐tumor immune effects, demonstrates high efficacy and safety in both in vitro and in vivo experiments. It provides a conceptual paradigm shift in nanomedicine‐mediated energy metabolism‐based tumor therapy.