Biointerface‐Engineered Hybrid Nanovesicles for Targeted Reprogramming of Tumor Microenvironment

Abstract The tumor microenvironment (TME) of typical tumor types such as triple‐negative breast cancer is featured by hypoxia and immunosuppression with abundant tumor‐associated macrophages (TAMs), which also emerge as potential therapeutic targets for antitumor therapy. M1‐like macrophage‐derived exosomes (M1‐Exos) have emerged as a promising tumor therapeutic candidate for their tumor‐targeting and macrophage‐polarization capabilities. However, the limited drug‐loading efficiency and stability of M1‐Exos have hindered their effectiveness in antitumor applications. Here, a hybrid nanovesicle is developed by integrating M1‐Exos with AS1411 aptamer‐conjugated liposomes (AApt‐Lips), termed M1E/AALs. The obtained M1E/AALs are loaded with perfluorotributylamine (PFTBA) and IR780, as P‐I, to construct P‐I@M1E/AALs for reprogramming TME by alleviating tumor hypoxia and engineering TAMs. P‐I@M1E/AAL‐mediated tumor therapy enhances the in situ generation of reactive oxygen species, repolarizes TAMs toward an antitumor phenotype, and promotes the infiltration of T lymphocytes. The synergistic antitumor therapy based on P‐I@M1E/AALs significantly suppresses tumor growth and prolongs the survival of 4T1‐tumor‐bearing mice. By integrating multiple treatment modalities, P‐I@M1E/AAL nanoplatform demonstrates a promising therapeutic approach for overcoming hypoxic and immunosuppressive TME by targeted TAM reprogramming and enhanced tumor photodynamic immunotherapy. This study highlights an innovative TAM‐engineering hybrid nanovesicle platform for the treatment of tumors characterized by hypoxic and immunosuppressive TME.