Besides 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.

中文翻译：

---

质子泵抑制剂通过诱导膜 v-ATP 酶组装增强巨胞饮介导的细胞外囊泡内吞作用

除了参与多种病理和生理过程外，细胞外囊泡（EV）也是出色的药物递送载体。然而，临床上仍缺乏调节EV水平的药物。在这里，我们表明质子泵抑制剂（PPI）通过增强巨胞饮介导的 EV 摄取来减少 EV。 PPI通过巨胞饮作用加速肠细胞对自分泌免疫抑制性EV的内吞，从而加重炎症性肠病。 PPI 诱导的巨胞饮作用有助于清除肿瘤细胞中的免疫抑制性 EV，从而提高抗肿瘤免疫力。 PPI诱导的巨胞饮作用还增加了EVs的阿霉素和microRNA-155反义寡核苷酸的递送效率，从而增强了载药EVs对肿瘤和急性肝衰竭的治疗效果。从机制上讲，质子泵抑制剂可降低胞质 pH 值，促进 ATP6V1A（v-ATP 酶亚基）从液泡膜上解体，增强质膜 v-ATP 酶的组装，从而诱导巨胞饮作用。总而言之，我们的结果揭示了巨胞饮调节机制和 PPI 作为 EV 水平的潜在调节剂，从而调节其功能。