Protein Corona Reprograms Hepatic Clearance Pathways of Biomimetic Nanoparticles via Ligand Masking and Differential Protein Enrichment

ABSTRACT Protein corona (PC) often leads to immune recognition and accelerated clearance of nanomedicines. Cell membrane‐coated nanoparticles (CM@NPs) have emerged as a biomimetic platform that enables prolonged circulation, immune evasion, and tissue targeting. However, the impact of PC formation on their hepatic fate remains underexplored. Here, we investigated how PC modulates hepatic clearance of CM@NPs. Magnetic silica nanoparticles were coated with red blood cell (RBC), macrophage (RAW264.7), or tumor cell (4T1) membranes to construct CM@NPs. Upon serum incubation, CM@NPs developed a PC that effectively masked key membrane ligands. Nano‐flow cytometry analysis revealed that 87.7% of CD47 on RBC@NPs and 73.7% of CD44 on 4T1@NPs were masked by adsorbed proteins. In vivo biodistribution studies demonstrated a clearance shift from Kupffer cells to hepatocytes: hepatocyte uptake increased to 50.6%–57.7% for CM@NPs compared with 41.1% for uncoated NPs, while Kupffer uptake decreased from 52.2% to 34.5%–46.7%. Proteomic profiling identified apolipoprotein A1 enrichment on CM@NPs, favoring hepatocyte recognition, whereas complement C4b and immunoglobulin G dominated the corona on uncoated NPs, promoting immune‐mediated clearance. These findings highlight the pivotal role of PC composition in modulating hepatic clearance pathways and provide mechanistic insights to guide rational design of CM@NPs for improved in vivo performance.