This study investigates the potential of exosomes as a drug delivery system to overcome multidrug resistance (MDR) in cancer cells. The researchers developed and characterized exosomes loaded with paclitaxel (PTX) using three methods: incubation at room temperature, electroporation, and mild sonication. The sonicated exosomes, referred to as exoPTX, showed the highest loading capacity and sustained drug release. In vitro studies demonstrated that exoPTX accumulated more efficiently in cancer cells compared to liposomes and polystyrene nanoparticles, and significantly increased cytotoxicity in both sensitive and resistant cancer cells. Mechanistically, exoPTX was found to bypass P-glycoprotein (Pgp)-mediated drug efflux by facilitating endosomal release of PTX. In vivo studies in a mouse model of pulmonary metastases showed that exoPTX effectively targeted and inhibited the growth of metastases, with near complete co-localization of exoPTX with cancer cells in the lungs. These findings suggest that exoPTX holds significant potential for treating drug-resistant cancers.This study investigates the potential of exosomes as a drug delivery system to overcome multidrug resistance (MDR) in cancer cells. The researchers developed and characterized exosomes loaded with paclitaxel (PTX) using three methods: incubation at room temperature, electroporation, and mild sonication. The sonicated exosomes, referred to as exoPTX, showed the highest loading capacity and sustained drug release. In vitro studies demonstrated that exoPTX accumulated more efficiently in cancer cells compared to liposomes and polystyrene nanoparticles, and significantly increased cytotoxicity in both sensitive and resistant cancer cells. Mechanistically, exoPTX was found to bypass P-glycoprotein (Pgp)-mediated drug efflux by facilitating endosomal release of PTX. In vivo studies in a mouse model of pulmonary metastases showed that exoPTX effectively targeted and inhibited the growth of metastases, with near complete co-localization of exoPTX with cancer cells in the lungs. These findings suggest that exoPTX holds significant potential for treating drug-resistant cancers.