An antifouling membrane-fusogenic liposome for effective intracellular delivery in vivo

The protein corona formed on the membrane-fusogenic liposome (MFlip) surface converts its membrane-fusion-based internalization to lysosome-dependent endocytosis, leading to the loss of delivery efficiency in the biological condition. To address this problem, we develop an antifouling MFlip (AFMFlip) for effective intracellular delivery in vivo. Leveraging the unique physicochemical characteristics and the optimized DOPC/DOTAP/DSPE-PEG ratio (90/5/5), AFMFlip effectively facilitates membrane fusion. Importantly, this fusion capacity is preserved in protein-rich conditions, attributed to the copious zwitterionic phosphorylcholine groups that inherently resist protein adsorption. Consequently, AFMFlip demonstrates robust membrane-fusion-mediated gene delivery in the medium with up to 38% fetal bovine serum, outclassing two traditional MFlips effective at 4% and 6% concentrations. When injected into mice, AFMFlip can keep their membrane-fusion-transportation behaviors in vivo, thereby achieving an effective luciferase transfection in the liver and enhancing CRISPR/Cas9-mediated treatment of hepatitis B virus infection. This AFMFlip serves as a promising tool for effective intracellular drug delivery under the complex physiological environment, providing great potential for future nanomedicine design.