Extending the In Vivo Residence Time of Macrophage Membrane‐Coated Nanoparticles through Genetic Modification

Abstract Nanoparticles coated with natural cell membranes have emerged as a promising class of biomimetic nanomedicine with significant clinical potential. Among them, macrophage membrane‐coated nanoparticles hold particular appeal due to their versatility in drug delivery and biological neutralization applications. This study employs a genetic engineering approach to enhance their in vivo residence times, aiming to further improve their performance. Specifically, macrophages are engineered to express proline‐alanine‐serine (PAS) peptide chains, which provide additional protection against opsonization and phagocytosis. The resulting modified nanoparticles demonstrate prolonged residence times when administered intravenously or introduced intratracheally, surpassing those coated with the wild‐type membrane. The longer residence times also contribute to enhanced nanoparticle efficacy in inhibiting inflammatory cytokines in mouse models of lipopolysaccharide‐induced lung injury and sublethal endotoxemia, respectively. This study underscores the effectiveness of genetic modification in extending the in vivo residence times of macrophage membrane‐coated nanoparticles. This approach can be readily extended to modify other cell membrane‐coated nanoparticles toward more favorable biomedical applications.