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

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 MSCs^4F-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 MSCs^4F-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.