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However, clinical drugs modulating EV levels are still lacking. Here, we show that proton pump inhibitors (PPIs) reduce EVs by enhancing macropinocytosis\u2010mediated EV uptake. PPIs accelerate intestinal cell endocytosis of autocrine immunosuppressive EVs through macropinocytosis, thereby aggravating inflammatory bowel disease. PPI\u2010induced macropinocytosis facilitates the clearance of immunosuppressive EVs from tumour cells, improving antitumor immunity. PPI\u2010induced macropinocytosis also increases doxorubicin and antisense oligonucleotides of microRNA\u2010155 delivery efficiency by EVs, leading to enhanced therapeutic effects of drug\u2010loaded EVs on tumours and acute liver failure. Mechanistically, PPIs reduce cytosolic pH, promote ATP6V1A (v\u2010ATPase subunit) disassembly from the vacuolar membrane and enhance the assembly of plasma membrane v\u2010ATPases, thereby inducing macropinocytosis. Altogether, our results reveal a mechanism for macropinocytic regulation and PPIs as potential modulators of EV levels, thus regulating their functions.<\/jats:p>","DOI":"10.1002\/jev2.12426","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T02:06:26Z","timestamp":1711505186000},"source":"Crossref","is-referenced-by-count":21,"title":["Proton pump inhibitors enhance macropinocytosis\u2010mediated extracellular vesicle endocytosis by inducing membrane v\u2010ATPase assembly"],"prefix":"10.1002","volume":"13","author":[{"given":"Xinliang","family":"Lu","sequence":"first","affiliation":[{"name":"Institute of Immunology and Bone Marrow Transplantation Center of the First Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"},{"name":"Institute of Hematology Zhejiang University &amp; Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy  Hangzhou 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