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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\u2010targeted 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\u2010bromopyruvate. Furthermore, combined intraperitoneal injection of L\u2010778123 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\u2010tumor immune effects, demonstrates high efficacy and safety in both in vitro and in vivo experiments. It provides a conceptual paradigm shift in nanomedicine\u2010mediated energy metabolism\u2010based tumor therapy.<\/jats:p>","DOI":"10.1002\/adhm.202405174","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T02:45:27Z","timestamp":1742179527000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["An Energy Metabolism Nanoblocker for Cutting Tumor Cell Respiration and Inhibiting Mitochondrial Hijacking from Cytotoxic T Lymphocyte"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-5849-4430","authenticated-orcid":false,"given":"Xiaojing","family":"Leng","sequence":"first","affiliation":[{"name":"Chongqing Key Laboratory of Ultrasound Molecular Imaging and Therapy Ultrasound Department of the Second Affiliated Hospital Institute of Ultrasound Imaging Chongqing Medical University  Chongqing 400010 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