Abstract

PEGylated lipid-based nanocarriers have significantly improved drug delivery efficiency while reducing toxicity. However, protein corona formation on the nano-surface alters their biological identity, resulting in unpredictable in vivo performance. In particular, binding of pre-existing anti-PEG antibodies can accelerate the blood clearance of PEGylated nanocarriers by complement activation and opsonization , leading to a drop in efficacy and unexpected adverse immune effects. Precisely modulating the composition and function of the protein corona can provide an effective approach to achieve efficient and safe drug delivery. Herein, we unraveled that discoid-shaped lipid nanodiscs displayed a unique protein corona pattern, demonstrating an entirely different biological fate from spherical liposomes . The discoid morphology considerably reduced complement binding and activation, enabling nanodiscs to evade the accelerated blood clearance phenomenon that severely impacts in vivo performance of most PEGylated nanocarriers. Furthermore, apolipoproteins preferentially adsorbed on the discoid surface along with their preserved functions and endowed nanodiscs with distinct brain targeting capability. Overall, the work presented here provides new insights into morphology-driven manipulation of the protein corona on the lipid-based nanocarriers for efficient preferential drug delivery.