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-l1KO 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.