Design of Mitoxantrone‐Loaded Biomimetic Nanocarrier with Sequential Photothermal/Photodynamic/Chemotherapy Effect for Synergized Immunotherapy

Abstract Metastatic triple‐negative breast cancer (TNBC) has a poor prognosis and high mortality with no effective treatment options, and immunotherapy is highly anticipated as a potential treatment but is limited by the lack of tumor‐infiltrating T lymphocytes in TNBC. Herein, red blood cell (RBC) membrane‐camouflaged polyphosphoester (PPE) nanoparticles (RBC@PPE_MTO/PFA) are prepared as the nanocarriers of mitoxantrone (MTO) and perfluoroalkane (PFA) for synergized immunotherapy. The encapsulated MTO can generate heat and reactive oxygen species (ROS) to achieve photothermal and photodynamic therapy; moreover, ROS further triggers the self‐accelerating release of MTO from the ROS‐sensitive PPE core to enable chemotherapy. The RBC@PPE_MTO/PFA‐mediated sequential photothermal/photodynamic/chemotherapy efficiently promotes the infiltration of CD8⁺ T cells into TNBC tumor tissue and synergizes the therapeutic activity of an immune checkpoint blockade antibody for metastatic TNBC treatment in distant and lung metastasis models. This biomimetic nanomedicine of MTO provides a convenient and available strategy to sensitize TNBC to immune checkpoint blockade antibody.