Alkaline phosphatase-responsive lipid-like polyphosphonitrile nanovesicles to enhance immunotherapy and inhibit metastasis of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is associated with high invasiveness and mortality, with current immunotherapies offering limited clinical benefits. Reduced tumor immunogenicity and dendritic cell (DC) dysfunction are major contributors to tumor immune evasion. Herein, an alkaline phosphatase (ALP)-responsive nanovesicle system (P-DOX/IFN-γ), based on lipid-like polyphosphonitrile (PEBP), was developed for the co-delivery of doxorubicin hydrochloride (DOX) and interferon-γ (IFN-γ), aiming to enhance the therapeutic efficacy against TNBC. The phosphate ester structure facilitates nanovesicle formation and enables multiple interactions with both drugs, thereby efficiently achieving the synchronous encapsulation of DOX within the membrane and IFN-γ in the aqueous cavity. P-DOX/IFN-γ exhibits enhanced tumor targeting and ALP-responsive drug release within the tumor microenvironment. Mechanistically, DOX induces immunogenic cell death in tumor cells, while IFN-γ induces cell cycle arrest and upregulates major histocompatibility complex class I (MHC I) expression, synergistically enhancing tumor immunogenicity and promoting DC activation. As a result, P-DOX/IFN-γ significantly amplifies antitumor immunity and reduces long-term postoperative metastasis in the orthotopic 4T1 tumor model. Overall, this study provides a versatile nanoplatform and a promising immunotherapeutic strategy for TNBC and other poorly immunogenic tumors.