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

Reprogrammingtumor-associated macrophages (TAMs) has emerged asa promising strategy in cancer immunotherapy. Targeted therapeuticsintegrating multiple functions to fully leverage the antitumor immunefunctions of macrophages without affecting systemic or tissue-residentmacrophages are crucial for TAM reprogramming. Herein, by integratingmolecular imprinting and nanotechnology, we rationally designed andengineered an unprecedented nanocoordinator for targeted remoldingof TAMs to fully leverage the antitumor efficacy of macrophages byinducing a cascade effect. The nanocoordinator features a magneticiron oxide nanoinner core and sialic acid-imprinted shell. Intravenouslyadministered into systemic circulation, the nanocoordinator can rapidlyaccumulate 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 retentiontime. Via binding with the nanocoordinator, tumor cells are taggedwith a foreign substance, which promotes the intrinsic phagocytosisof macrophages. Subsequently, the nanocoordinator taken up by macrophageseffectively promotes the polarization of macrophages toward the M1phenotype, thus activating the immunotherapeutic efficacy of macrophages.Synergized by the cascade effect, this nanocoordinator effectivelyharnesses TAMs for macrophage-mediated immunotherapy. This study offersnew TAM-targeted therapeutics that allows us to fully leverage theantitumor immune functions of macrophages without affecting the normaltissue.