Macrophage Phenotype-Dependent Protein Corona Formation Governs Ligand Accessibility and Immune Clearance of...

The phenotype of source cells used for membrane coating fundamentally influences the biointerfacing behavior of cell membrane-coated nanoparticles. Meanwhile, the formation of a protein corona (PC) in biological fluids plays a pivotal role in dictating the in vivo fate of nanoparticles. Yet, how macrophage phenotypes influence PC composition and, in turn, dictate the clearance of biomimetic nanoparticles remains underexplored. Here, we prepared magnetic silica nanoparticles (SMNs) coated with membranes from M0, M1, and M2 macrophages (denoted as M0@SMNs, M1@SMNs, and M2@SMNs) to elucidate phenotype-dependent PC fingerprints and their impact on immune recognition and clearance. In vivo and in vitro studies demonstrated that M0@SMNs exhibited superior immune evasion, reduced hepatic clearance, and prolonged blood retention. Nano-flow cytometry revealed that PC formation masked up to ≈40% of surface membrane proteins. Furthermore, proteomics, Western blotting, and ELISA analyses confirmed that M0@SMNs exhibited minimal adsorption of immune opsonins (C3, IgG, IgM) and triggered the lowest complement activation, which account for their attenuated hepatic clearance. Collectively, these findings identify source cell phenotype as a key determinant of PC composition and clearance fate, thereby offering mechanistic guidance for the rational design of biomimetic nanocarriers. Notably, M0 macrophages confer superior systemic circulation relative to M1 and M2 counterparts.