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However, the therapeutic efficacy of MSCs is significantly hindered by low cell viability and suboptimal retention at the implantation site. Herein, a bio\u2010orthogonal strategy that covalently integrates MSCs with chitosan for nerve regeneration is presented. In vitro analysis revealed covalent combination enhanced adhesion and survival of MSCs on chitosan scaffolds via phosphoinositide 3\u2010kinase (PI3K) and protein kinase B (Akt) signaling pathway. Quantitative proteomics confirmed that these MSCs enhance the secretion of key neurotrophic factors for neuroregeneration. In vivo investigations utilizing a nerve crush injury model demonstrated that bio\u2010orthogonal\u2010mediated MSC therapy markedly improves cell retention at the lesion site. Furthermore, this innovative strategy actively modulates the immune microenvironment, accelerates Wallerian degeneration, promotes angiogenesis, and remodels the extracellular matrix, thereby expediting repair processes following peripheral nerve injury. Specifically, further evaluation utilizing a 10\u00a0mm sciatic nerve transection model demonstrated that the bio\u2010orthogonal strategy significantly enhanced the therapeutic efficacy of MSCs. Collectively, the approach developed in this study provides a simple, efficient, and translatable strategy for augmenting MSC\u2010mediated peripheral nerve repair. This work lays a solid theoretical foundation for the future clinical application of chitosan\u2010MSC composite materials in neuroregenerative medicine.<\/jats:p>","DOI":"10.1002\/adma.202523237","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T11:13:17Z","timestamp":1769685197000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Bio\u2010Orthogonal Engineered Chitosan Platform for Enhanced Mesenchymal Stem Cells Delivery and Function in Peripheral Nerve Repair"],"prefix":"10.1002","volume":"38","author":[{"given":"Xueying","family":"Zhao","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of Tissue Engineering and Neuroregeneration Co\u2010innovation Center of Neuroregeneration NMPA Key Laboratory For Research and Evaluation of Tissue Engineering Technology Products Key Laboratory of Neuroregeneration of Ministry of Education Medical School of Nantong University Nantong University  Nantong P. 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