Cross-species hybrid vesicles enable synergistic immunochemotherapy through enhanced targeted drug delivery and immune activation

To overcome the critical challenges of insufficient drug targeting and restricted dendritic cell (DC) activation in chemo-immunotherapy, this study developed an innovative cross-species hybrid vesicle delivery system. By fusing extracellular vesicles derived from 4T1 tumor cells (TEV) with kiwifruit-derived extracellular vesicles (KEV), we constructed a homologous targeting hybrid vesicle carrier (TKEV). This platform was co-loaded with chemotherapeutic agent doxorubicin (DOX) and Bcl-2 siRNA (siBcl2) to form a combination therapeutic system (TKDS). Key findings demonstrate: (1) TKDS achieves precise tumor-targeted delivery, significantly enhancing tumor cell apoptosis through combined chemo-gene therapy; (2) The KEV component effectively stimulated DC maturation, enhanced antigen presentation, and increased CD8+ T cell infiltration in tumors; (3) In a 4T1 murine breast cancer models, TKDS significantly enhanced antitumor efficacy through synergistic immunochemotherapy. To our knowledge, this work provides the first evidence that a cross-species vesicle fusion strategy can simultaneously enhance drug targeting and immune activation, offering a versatile and promising platform for developing highly effective and safer immunochemotherapy regimens.