Comparative Proteomics Inspired Self‐Stimulated Release Hydrogel Reinforces the Therapeutic Effects of MSC‐EVs on Alzheimer's Disease

Abstract The clinical application of extracellular vesicles (EVs)‐based therapeutics continues to be challenging due to their rapid clearance, restricted retention, and low yields. Although hydrogel possesses the ability to impede physiological clearance and increase regional retention, it typically fails to effectively release the incorporated EVs, resulting in reduced accessibility and bioavailability. Here an intelligent hydrogel in which the release of EVs is regulated by the proteins on the EVs membrane is proposed. By utilizing the EVs membrane enzyme to facilitate hydrogel degradation, sustained retention and self‐stimulated EVs release can be achieved at the administration site. To achieve this goal, the membrane proteins with matrix degrading activity in the mesenchymal stem cell‐derived extracellular vesicles (MSC‐EVs) are identified using comparative proteomics. After that, a hydrogel comprised of self‐assembled peptides that are susceptible to degradation by the membrane enzymes present in MSC‐EVs is designed and synthesized. After intranasal administration, this peptide hydrogel facilitates sustained and thermo‐sensitive release of MSC‐EVs, thereby extending the retention of the MSC‐EVs and substantially enhancing their potential for treating Alzheimer's disease. This research presents a comparative proteomics‐driven approach to intelligent hydrogel design, which holds the capacity to significantly enhance the applicability of EVs in clinical settings.