Immunogenic Nanovesicle‐Tandem‐Augmented Chemoimmunotherapy via Efficient Cancer‐Homing Delivery and Optimized Ordinal‐Interval Regime

Abstract The strategy of combining immune checkpoint inhibitors (ICIs) with anthracycline is recommended by clinical guidelines for the standard‐of‐care treatment of triple‐negative breast cancer (TNBC). Nevertheless, several fundamental clinical principles are yet to be elucidated to achieve a great therapeutic effect, including cancer‐homing delivery efficiency and ordinal‐interval regime. Tumor‐derived extracellular vesicles (TDEVs), as vectors for intratumoral intercellular communication, can encapsulate therapeutic agents and home tumors. However, PD‐L1 overexpression in TDEVs leads to systemic immunosuppression during in vivo circulation, ultimately inhibiting intratumoral T activity. In this study, CRISPR/Cas9‐edited Pd‐l1^KO TDEV‐fusogenic anthracycline doxorubicin (DOX) liposomes with high drug encapsulation (97%) are fabricated, which homologously deliver DOX to breast cancer cells to intensify the immunogenic response and induce PD‐L1 overexpression in the tumor. By setting the stage for sensitizing tumors to ICIs, sequential treatment with disulfide‐linked PD1‐cross‐anchored TDEVs nanogels at one‐day interval could sustainably release PD1 in the tumor, triggering a high proportion of effector T cell‐mediated destruction of orthotopic and metastatic tumors without off‐target side effects in the 4T1‐bearing TNBC mouse model. Such a TDEV‐tandem‐augmented chemoimmunotherapeutic strategy with efficient cancer‐homing delivery capacity and optimized ordinal‐interval regime provides a solid foundation for developing chemoimmunotherapeutic formulations for TNBC therapy at the clinical level.