Institute of Immunology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, China.
J Extracell Vesicles. 2024 Apr;13(4):e12426. doi: 10.1002/jev2.12426.
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.
除了参与多种病理和生理过程外，细胞外囊泡 (EVs) 也是出色的药物递送载体。然而，能够调节 EV 水平的临床药物仍然缺乏。在这里，我们发现质子泵抑制剂 (PPIs) 通过增强巨胞饮介导的 EV 摄取来降低 EV 水平。PPIs 通过巨胞饮加速肠道细胞内自体免疫抑制性 EV 的内吞作用，从而加重炎症性肠病。PPI 诱导的巨胞饮促进了肿瘤细胞中免疫抑制性 EV 的清除，从而增强了抗肿瘤免疫。PPI 诱导的巨胞饮还通过 EV 增加了多柔比星和 microRNA-155 反义寡核苷酸的递送效率，从而提高了载药 EV 对肿瘤和急性肝衰竭的治疗效果。从机制上讲，PPIs 降低了细胞质 pH 值，促进了液泡膜上 ATP6V1A（v-ATPase 亚基）的解体，并增强了质膜 v-ATPase 的组装，从而诱导了巨胞饮。总的来说，我们的结果揭示了巨胞饮调节的机制以及 PPIs 作为 EV 水平的潜在调节剂，从而调节它们的功能。
