Abstract
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.