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Herein, a biomimetic drug delivery system based on lemon\u2010derived extracellular vesicles (EVs) nanodrugs (marked with heparin\u2010cRGD\u2010EVs\u2010doxorubicin (HRED)) is demonstrated, achieving highly efficient overcoming cancer multidrug resistance. The HRED is fabricated by modifying functional heparin\u2010cRGD (HR) onto the surface of EVs and then by loading with doxorubicin (DOX). The obtained HRED enable to effectively enter DOX\u2010resistant cancer cells by caveolin\u2010mediated endocytosis (main), macropinocytosis (secondary), and clathrin\u2010mediated endocytosis (last), exhibiting excellent cellular uptake capacity. The diversified endocytosis capacity of HRED can efficiently dissipate intracellular energy and meanwhile trigger downstream production reduction of adenosine triphosphate (ATP), leading to a significant reduction of drug efflux. Consequently, they show excellent anti\u2010proliferation capacities to DOX\u2010resistant ovarian cancer, ensuring the efficiently overcoming ovarian cancer multidrug resistance in vivo. The authors believe this strategy provides a new strategy by endocytosis triggered\u2010energy dissipation and ATP production reduction to design drug delivery system for overcoming cancer multidrug resistance.<\/jats:p>","DOI":"10.1002\/advs.202105274","type":"journal-article","created":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T02:15:05Z","timestamp":1645409705000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":173,"title":["Lemon\u2010Derived Extracellular Vesicles Nanodrugs Enable to Efficiently Overcome Cancer Multidrug Resistance by Endocytosis\u2010Triggered Energy Dissipation and Energy Production Reduction"],"prefix":"10.1002","volume":"9","author":[{"given":"Qian","family":"Xiao","sequence":"first","affiliation":[{"name":"Cancer Research Institute Experimental Education\/Administration Center School of Basic Medical Sciences Southern Medical University  Guangzhou 510515 P. R. 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