Enzymatic Surface Shielding of MSCs Boosts In Vivo Retention and Neuroprotection Against Alzheimer’s Disease

Wang Liao, Mengyao Ji, Leyan Xuan, et al.
The Second Affiliated Hospital of Guangzhou Medical University

Background:
Mesenchymal stem cells hold promise for Alzheimer’s disease therapy, but their efficacy is limited by poor survival, rapid clearance, and insufficient in vivo retention after systemic administration.

Strategy:
We developed a microbial transglutaminase-mediated single-cell encapsulation strategy to engineer a thin gelatin hydrogel shell around individual MSCs, generating MSC@Gel as a protective cellular interface.

Key Findings:
MSC@Gel formed a continuous gelatin shell around individual MSCs while preserving cell viability and cytoskeletal integrity. The gelatin shell reduced oxidative stress-induced ROS accumulation, preserved mitochondrial membrane potential, and improved survival under shear stress. After intravenous administration, MSC@Gel showed markedly prolonged in vivo retention compared with uncoated MSCs, with an estimated retention half-life of 74.3 h versus approximately 28–33 h for bare MSCs. In 5xFAD mice, MSC@Gel improved recognition memory and spatial learning, reduced Aβ plaque deposition, attenuated IBA-1-positive microglial activation, and preserved neuronal integrity.

Conclusion:
Enzymatic surface shielding enhances MSC persistence and neuroprotective efficacy, providing a low-dose, high-efficacy cell-engineering strategy for Alzheimer’s disease.