Exosomes, naturally occurring membrane vesicles, have been explored as efficient drug delivery vehicles for cancer treatment, particularly for overcoming multidrug resistance (MDR). This study developed and characterized exosome-encapsulated paclitaxel (exoPTX) as a potential therapy for MDR cancers. Exosomes were loaded with paclitaxel using three methods: incubation, electroporation, and sonication. Sonication provided the highest drug loading efficiency and sustained release. ExoPTX showed significantly increased cytotoxicity in drug-resistant MDCK-MDR1 cells compared to free paclitaxel. In a murine model of pulmonary metastases, exoPTX demonstrated efficient targeting of cancer cells and potent anticancer effects. Exosomes were found to co-localize with cancer cells in the lungs, indicating effective delivery of the drug. The study also showed that exoPTX bypasses P-glycoprotein (Pgp)-mediated drug efflux, enhancing its therapeutic efficacy in resistant cancer cells. Exosomes offer advantages over synthetic nanocarriers, including reduced clearance and immune response, and their ability to deliver drugs to target cells. The results suggest that exoPTX has significant potential for treating drug-resistant cancers.Exosomes, naturally occurring membrane vesicles, have been explored as efficient drug delivery vehicles for cancer treatment, particularly for overcoming multidrug resistance (MDR). This study developed and characterized exosome-encapsulated paclitaxel (exoPTX) as a potential therapy for MDR cancers. Exosomes were loaded with paclitaxel using three methods: incubation, electroporation, and sonication. Sonication provided the highest drug loading efficiency and sustained release. ExoPTX showed significantly increased cytotoxicity in drug-resistant MDCK-MDR1 cells compared to free paclitaxel. In a murine model of pulmonary metastases, exoPTX demonstrated efficient targeting of cancer cells and potent anticancer effects. Exosomes were found to co-localize with cancer cells in the lungs, indicating effective delivery of the drug. The study also showed that exoPTX bypasses P-glycoprotein (Pgp)-mediated drug efflux, enhancing its therapeutic efficacy in resistant cancer cells. Exosomes offer advantages over synthetic nanocarriers, including reduced clearance and immune response, and their ability to deliver drugs to target cells. The results suggest that exoPTX has significant potential for treating drug-resistant cancers.