Dichotomous role of CD47–SIRPα axis: Leveraging opposing functions in phagocytic resistance and transport assistance for enhanced nanocarrier biocompatibility and tumor penetration

Polyethylene glycol (PEG) carriers can improve drug circulation, but encounter biocompatibility and tumor penetration challenges. The CD47–SIRP α interaction on macrophages can initiate a “don’t-eat-me” signal, inhibiting phagocytosis. This study elucidates the dichotomous role of the CD47–SIRP α 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 SIRP α 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–SIRP α 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–SIRP α axis in regulating carrier biocompatibility, offering insights into its function to overcome the tumor permeability barrier challenge. The CD47–SIRP α axis enhances carrier biocompatibility by inhibiting nanocarrier endocytosis by macrophages and facilitates deep tumor penetration while modulating the tumor microenvironment via M1/M2 macrophage differential recognitions.