“AND” Logic-Gated Biomimetic Nanoparticles to Activate Macrophage Phagocytosis for Cancer Immunotherapy

Macrophages eliminate abnormal cells through phagocytosis, yet their phagocytic ability toward tumor cells is hindered by elevated "don't eat me" signals (e.g., CD47) and insufficient pro-phagocytic signals (e.g., calreticulin, CRT) within the tumor microenvironment. Efficient modulation of macrophage phagocytosis remains a key challenge for immunotherapies. Here, we propose an "AND" logic-gated strategy based on biomimetic nanoparticles to enhance macrophage phagocytosis for improved cancer immunotherapy. The hybrid cell-membrane nanovesicles (Fus-CMVs) were constructed by fusing plasma membranes from engineered 293T cells expressing a high-affinity SIRPα variant to block CD47 (Signal A) with membranes from doxorubicin-pretreated 4T1 tumor cells to display CRT (Signal B). In vitro and in vivo studies demonstrated that the "AND" logic-gated Fus-CMVs significantly increased macrophage engulfment of tumor cells and remarkably inhibited tumor growth in different tumor models when compared with single-signal controls. This approach offers a promising approach to enhance macrophage-mediated antitumor immunotherapy.