Phagocytosis‐Activating Nanocomplex Orchestrates Macrophage‐Mediated Cancer Immunotherapy

Abstract The phagocytosis of macrophages to tumor cells represents an alluring strategy for cancer immunotherapy; however, its effectiveness is largely hindered by the detrimental upregulation of anti‐phagocytic signals and insufficient expression of pro‐phagocytic signals of tumor cells. Here, a pro‐phagocytic polymer‐based nanocomplex is designed to promote the macrophage engulfment of tumor cells through concurrent modulation of both the “eat me” and “don't eat me” signals. The nanocomplex MNC CD47i‐CALRt is formed by complexing a synthetic PAMAM derivative (G4P–C7A) that is capable of intrinsically inducing the exposure of calreticulin (CALR, a crucial pro‐phagocytic protein) and a small inference RNA that can inhibit the expression of CD47 (a primary anti‐phagocytic protein). MNC CD47i‐CALRt can significantly delay tumor growth and prolong the survival of tumor‐bearing mice with negligible hematopoietic toxicity in multiple murine colorectal cancer models. Furthermore, the pro‐phagocytic capacity of MNC CD47i‐CALRt is validated in the patient‐derived tumor organoid model. Collectively, the phagocytosis‐promoting nanocomplex provides a simple and potent strategy for boosting macrophage‐mediated cancer immunotherapy.