Dual‐Targeted Biomimetic Hybrid Nanovesicles for Tumor Microenvironment Reprogramming and Intratumoral Bacteria Eradication in Triple‐Negative Breast Cancer

Abstract Fusobacterium nucleatum ( F. nucleatum ), a critical intratumoral pathogen of triple‐negative breast cancer, is closely related to chemotherapeutic drug resistance, immunosuppression, and tumor metastasis. Herein, the F. nucleatum ‐4T1 hybrid cell membrane vesicle (HMV) functional lipid nanoparticles is developed and decorated them with antitumor RS17 peptide, which are designed to codelivery chemotherapeutic drug doxorubicin, photosensitizer IR820, and immunomodulator polymetformin (DPI@HMV‐RS17). The dual targeting ability of HMV and RS17 peptide results in targeted accumulation of DPI@HMV‐RS17 in the tumor site to precisely kill intratumoral bacteria and tumor cells. Additionally, DPI@HMV‐RS17 can induce immunogenic cell death, resulting in enhanced immunogenicity and further facilitating the maturation of dendritic cells and cytotoxic T‐cell infiltration. Moreover, DPI@HMV‐RS17 can effectively induce macrophages into the M1‐like phenotype by blocking CD47‐SIRPα signaling, resulting in the phagocytosis of tumor cells. Therefore, the immunosuppressive tumor microenvironment is reversed, significantly enhancing the antitumor immune response. Upon laser irradiation, DPI@HMV‐RS17 showed excellent antitumor effects in the F. nucleatum ‐colonized 4T1 breast tumor models through the close synergy among each component, which not only inhibited tumor growth but also prevented lung metastasis and tumor recurrence, providing new insights and potential application prospects in boosting the immunotherapy of bacteria‐colonized tumors.