Dual‐Targeted M1 Macrophage Extracellular Vesicles Reprogram the Tumor Microenvironment and Enhance Natural Killer Cell Immunotherapy in Breast Cancer

ABSTRACT Breast cancer is the most commonly diagnosed cancer worldwide and a leading cause of cancer‐related mortality in women. Despite therapeutic advances, treating advanced or recurrent cases is substantially hampered by drug resistance and the immunosuppressive tumor microenvironment (TME). Here, we report a breakthrough immunotherapeutic strategy using dual‐targeted extracellular vesicles from pro‐inflammatory M1 macrophages, hyaluronic acid (HA), and cyclic RGD (M1EV_HA/cRGD), which function as molecular bridges to physically link natural killer (NK) cells with cancer cells. Our platform simultaneously reprograms the hostile TME while activating potent antitumor immunity. HA is incorporated to engage CD44 receptors on NK cells and cRGD peptides to bind tumor‐overexpressing integrins, establishing precision dual‐targeting. M1EV_HA/cRGD could physically tether NK cells directly to tumors, and deliver inflammatory cytokines and miRNAs that transform the immunosuppressive TME into a pro‐inflammatory battlefield, substantially amplifying immune activation. In vitro and in vivo studies demonstrate that M1EV_HA/cRGD significantly enhances NK cell clustering at tumor sites, activation status, and cytotoxic killing of breast cancer cells. Unlike single‐targeted approaches, this dual‐targeting mechanism achieves simultaneous TME reprogramming and enhanced immune‐tumor engagement. M1EV_HA/cRGD is a paradigm shift in solid tumor immunotherapy that directly addresses breast cancer treatment failure, can overcome therapeutic resistance, and substantially improve patient survival outcomes.