Proton pump inhibitors enhance macropinocytosis‐mediated extracellular vesicle endocytosis by inducing membrane v‐ATPase assembly

Abstract

AbstractBesides participating in diverse pathological and physiological processes, extracellular vesicles (EVs) are also excellent drug‐delivery vehicles. However, clinical drugs modulating EV levels are still lacking. Here, we show that proton pump inhibitors (PPIs) reduce EVs by enhancing macropinocytosis‐mediated EV uptake. PPIs accelerate intestinal cell endocytosis of autocrine immunosuppressive EVs through macropinocytosis, thereby aggravating inflammatory bowel disease. PPI‐induced macropinocytosis facilitates the clearance of immunosuppressive EVs from tumour cells, improving antitumor immunity. PPI‐induced macropinocytosis also increases doxorubicin and antisense oligonucleotides of microRNA‐155 delivery efficiency by EVs, leading to enhanced therapeutic effects of drug‐loaded EVs on tumours and acute liver failure. Mechanistically, PPIs reduce cytosolic pH, promote ATP6V1A (v‐ATPase subunit) disassembly from the vacuolar membrane and enhance the assembly of plasma membrane v‐ATPases, thereby inducing macropinocytosis. Altogether, our results reveal a mechanism for macropinocytic regulation and PPIs as potential modulators of EV levels, thus regulating their functions.