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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. [ABSTRACT FROM AUTHOR]

This work introduces a novel multifunctional system called UPIPF (upconversion‐polydopamine‐indocyanine‐polyethylene‐folic) for upconversion luminescent (UCL) imaging of cancer cells using near‐infrared (NIR) illumination. The system demonstrates efficient inhibition of human hepatoma (HepG2) cancer cells through a combination of NIR‐triggered photodynamic therapy (PDT) and enhanced photothermal therapy (PTT). Initially, upconversion nanoparticles (UCNP) are synthesized using a simple thermal decomposition method. To improve their biocompatibility and aqueous dispersibility, polydopamine (PDA) is introduced to the UCNP via a ligand exchange technique. Indocyanine green (ICG) molecules are electrostatically attached to the surface of the UCNP‐polydopamine (UCNP@PDAs) complex to enhance the PDT and PTT effects. Moreover, polyethylene glycol (PEG)‐modified folic acid (FA) is incorporated into the UCNP‐polydopamine‐indocyanine‐green (UCNP@PDA‐ICGs) nanoparticles to enhance their targeting capability against cancer cells. The excellent UCL properties of these UCNP enable the final UCNP@PDA‐ICG‐PEG‐FA nanoparticles (referred to as UPIPF) to serve as a potential candidate for efficient anticancer drug delivery, real‐time imaging, and early diagnosis of cancer cells. Furthermore, the UPIPF system exhibits PDT‐assisted PTT effects, providing a convenient approach for efficient cancer cell inhibition (more than 99% of cells are killed). The prepared UPIPF system shows promise for early diagnosis and simultaneous treatment of malignant cancers. [ABSTRACT FROM AUTHOR]