Pathogen‐Mimetic Liposomes Customizing Protein Corona for Precision Glioblastoma Therapy

Employing neutrophils (NEs) as endogenous moving gears offers a promising strategy for crossing the blood-brain barrier (BBB) in the treatment of central nervous system (CNS) malignancies such as glioblastoma (GBM). However, in vivo hitchhiking efficiency of NEs is severely limited by spontaneous formation of a nonspecific protein corona. Here, we present pathogen-mimetic liposomes (PM-Lipo) that enable efficient and precise NEs hitchhiking by programming the in vivo protein corona. PM-Lipo is rationally engineered to preferentially enrich complement 3b (C3b) and inactivated C3b (iC3b), thereby recapitulating endogenous complement opsonization and promoting complement receptor 3 (CR3)-mediated recognition by activated NEs. This effect arises from the synergistic integration of two functional lipids that activate distinct complement pathways, triggering a proteolytic cascade with positive feedback to amplify C3b/iC3b deposition. Our results demonstrate that PM-Lipo achieved >85% targeting efficiency toward activated NEs, enabling hitchhiking-mediated transport across the BBB, with 8.94% of the administered PM-Lipo successfully penetrating the brain, leading to marked tumor suppression and more than a twofold extension in median survival. Our research establishes a protein corona programming strategy to harness endogenous immune cells for targeted drug delivery, offering a broadly applicable paradigm for precision nanomedicine in CNS malignancies.