Polyethylene glycol (PEG) carriers can improve drug circulation, but encounter biocompatibility and tumor penetration challenges. The CD47-SIRPα interaction on macrophages can initiate a “don't-eat-me” signal, inhibiting phagocytosis. This study elucidates the dichotomous role of the CD47-SIRPα axis in conferring phagocytosis resistance and transport assistance for enhanced nanocarrier biocompatibility and tumor penetration. Using CD47-functional peptide, we elucidated the capacity of this axis to preserve carrier-cell membrane accessibility, impede macrophage-mediated nanocarrier endocytosis, reduce the secretion of IgG and IgM antibodies, and attenuate complement cascade activation. These mechanisms collectively neutralize the accelerated blood clearance of PEGylated liposomes. Notably, we identified the presence of SIRPα in endothelial vasculature and, for the first time, verified its pivotal role in orchestrating liposomal transit across the endothelial barrier. Moreover, within the tumor region, the CD47-SIRPα axis facilitated carrier hitchhiking on macrophages, enabling deep penetration into the tumor parenchyma and regulating the tumor microenvironment through the differential recognition of M1/M2-type tumor-associated macrophages. This study presents the first evidence of the dichotomous role of the CD47-SIRPα axis in regulating carrier biocompatibility, offering insights into its function to overcome the tumor permeability barrier challenge.

Liposome  /  Polyethylene glycol  /  Accelerated blood clearance phenomenon  /  CD47  /  Endothelial cell  /  Tumor microenvironment