A Biomimetic Nanogel System Restores Macrophage Phagocytosis for Magnetic Resonance Imaging‐Guided Synergistic Chemoimmunotherapy of Breast Cancer

Novel strategies to facilitate tumor-specific drug delivery and restore immune attacks remain to be developed to overcome the current limitations of chemotherapy. Herein, a cancer cell membrane (CM)-camouflaged and ultrasmall iron oxide nanoparticles (USIO NPs)-loaded polyethylenimine nanogel (NG) system is reported to co-deliver docetaxel (DTX) and CD47 siRNA (siCD47). The prepared co-delivery system exhibits good colloidal stability, biocompatibility, and r1 relaxivity (1.35 mM-1 s-1 ) and enables redox-responsive release of the loaded DTX in the tumor microenvironment. The NG system realizes homologous targeting delivery of DTX and siCD47 to murine breast cancer cells (4T1 cells) for efficient chemotherapy and gene silencing; thus, inducing immunogenic cell death (ICD) and restoring macrophage phagocytic effect through downregulation of "don't eat me" signals on cancer cells. Likewise, the co-delivery system can also act on macrophages to promote their M1 polarization, which can be combined with DTX-mediated ICD and antibody-mediated immune checkpoint blockade to generate effector T cells for robust chemoimmunotherapy. Further, the USIO NPs-incorporated NG system also allows for magnetic resonance imaging of tumors. The developed biomimetic NG system acting on both cancer cells and macrophages holds a promising potential for macrophage phagocytosis-restored chemoimmunotherapy.