Pathogen‐Mimetic Liposomes Customizing Protein Corona for Precision Glioblastoma Therapy

Vollständiger Abstract

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ABSTRACT 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.