A pH-triggered fluorescence-switchable extracellular vesicle for tracing drug release and improving drug delivery

Extracellular vesicles have shown great potential in drug delivery for clinical applications. However, some obstacles still need to be overcome before their clinical translation, including on demand release of drugs to improve the efficacy and monitoring of the drug release process to ascertain drug dosage. Herein, a pH-triggered fluorescence-switchable extracellular vesicle as a smart nanocarrier is fabricated by loading zwitterionic fluorescent carbon dots (CDs) into macrophage cell-secreted vesicles to achieve improved drug delivery and real-time monitoring of drug release. When circulating in the blood, the zwitterionic CDs loaded in the vesicles can tightly bind the chemotherapeutic drug DOX through electrostatic interactions to avoid premature drug unload. The nanocarriers have a long blood circulation half-life of 15.12 h and a high tumor accumulation of 9.88% ID/g. Meanwhile, the fluorescence of the CDs is in the "off" state due to the fluorescence inner filter effect (IFE) between the DOX and the CDs. When the nanocarriers enter the tumor cells, the low pH of the lysosome leads to charge reversal of the CDs. DOX can be quickly released through electrostatic repulsion and the fluorescence of the CDs turns "on" after the release of the drugs, thus enabling an improved drug delivery and real-time tracking of the drug release process.