Phagocytosis-Activating Nanocomplex Orchestrates Macrophage-Mediated Cancer Immunotherapy

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.