Hierarchical Zeolitic Imidazolate Framework-8@Au Cluster Nanocarriers for In Situ Chimeric Antigen Receptor Macrophage Programming and Immunotherapy in Prostate Cancer.

Chimeric antigen receptor-T (CAR-T) adoptive transfer therapy has shown remarkable efficacy in hematologic malignancies. However, the therapeutic efficacy of CAR-T in treating solid tumors, particularly "cold tumors" such as prostate cancer, is significantly restricted by the cumbersome ex vivo manufacturing, impaired T cell fitness, and an immunosuppressive tumor microenvironment that blunts T cell function. Here, we successfully constructed a nanodelivery system based on zeolitic imidazolate framework-8 (ZIF-8). This system exhibited high CAR-gene encapsulation efficiency, reduced nonspecific hepatic accumulation, targeted delivery to tumor-associated macrophages (TAMs), and efficient intracellular gene transfection efficiency, enabling in situ construction of chimeric antigen receptor macrophage (CAR-M). Co-delivery of IFN-γ and CAR genes not only maintained the specific tumor-killing and phagocytic activity of CAR-Ms against tumor cells but also activated adaptive immunity, inducing excellent antitumor efficacy, as evidenced by the observed 95.54% inhibition of tumor growth in a prostate cancer mouse model. This strategy provides a promising approach for systematic in vivo editing of CAR-Ms.