Leveraging Macrophage-Mediated Cancer Immunotherapy via a Cascading Effect Induced by a Molecularly Imprinted Nanocoordinator

Reprogramming tumor-associated macrophages (TAMs) has emerged as a promising strategy in cancer immunotherapy. Targeted therapeutics integrating multiple functions to fully leverage the antitumor immune functions of macrophages without affecting systemic or tissue-resident macrophages are crucial for TAM reprogramming. Herein, by integrating molecular imprinting and nanotechnology, we rationally designed and engineered an unprecedented nanocoordinator for targeted remolding of TAMs to fully leverage the antitumor efficacy of macrophages by inducing a cascade effect. The nanocoordinator features a magnetic iron oxide nanoinner core and sialic acid-imprinted shell. Intravenously administered into systemic circulation, the nanocoordinator can rapidly accumulate at the tumor site in response to an external magnet. Then, by specifically binding to sialic acid overexpressed on tumor cells, the nanocoordinator anchors at the tumor site with prolonged retention time. Via binding with the nanocoordinator, tumor cells are tagged with a foreign substance, which promotes the intrinsic phagocytosis of macrophages. Subsequently, the nanocoordinator taken up by macrophages effectively promotes the polarization of macrophages toward the M1 phenotype, thus activating the immunotherapeutic efficacy of macrophages. Synergized by the cascade effect, this nanocoordinator effectively harnesses TAMs for macrophage-mediated immunotherapy. This study offers new TAM-targeted therapeutics that allows us to fully leverage the antitumor immune functions of macrophages without affecting the normal tissue.