A Nanodisc‐Paved Biobridge Facilitates Stem Cell Membrane Fusogenicity for Intracerebral Shuttling and Bystander Effects

Abstract Mesenchymal stem cell (MSC) therapies experience steadfast clinical advances but are still hindered by inefficient site‐specific migration. An adaptable MSC membrane fusogenicity technology is conceptualized for lipid raft‐mediated targeting ligand embedding by using toolkits of discoidal high‐density lipoprotein (HDL)‐containing biomimicking 4F peptides. According to the pathological clues of brain diseases, the vascular cell adhesion molecule 1 specialized VBP peptide is fused with 4F to assemble 4F‐VBP (HDL), which acts as a biobridge and transfers VBP onto the living cell membrane via lipid rafts for surface engineering of MSCs in suspension. When compared with the membrane‐modifying strategies of PEGylated phospholipids, 4F‐VBP (HDL) provides a 3.86 higher linkage efficiency to obtain MSCs4F–VBP(HDL), which can recognize and adhere to the inflammatory endothelium for efficient blood–brain barrier crossing and brain accumulation. In APPswe/PSEN1dE9 mice with Alzheimer's disease (AD), the transcriptomic analysis reveals that systemic administration of MSCs4F–VBP(HDL) can activate pathways associated with neuronal activity and diminish neuroinflammation for rewiring AD brains. This customizable HDL‐mediated membrane fusogenicity platform primes MSC inflammatory brain delivery, which can be expanded to other disease treatments by simply fusing 4F with relevant ligands for living cell engineering.