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Among these challenges, achieving axon regeneration and functional recovery post\u2010injury or disease in the central nervous system remains elusive to most clinical interventions, constantly calling for innovative solutions. Here, a thermally responsive hydrogel system utilizing recombinant spider silk protein (spidroin) is developed. The protein solution undergoes rapid sol\u2010gel transition at an elevated temperature (37\u00a0\u00b0C) following brief sonication. This thermally triggered gelation confers injectability to the system. Leveraging SpyTag\/SpyCatcher chemistry, the hydrogel, composed of SpyTag\u2010fusion spidroin, can be functionalized with diverse SpyCatcher\u2010fusion bioactive motifs, such as neurotrophic factors (e.g., ciliary neurotrophic factor) and cell\u2010binding ligands (e.g., laminin), rendering it well\u2010suited for neuronal culturing. More importantly, the intravitreous injection of the protein materials decorated with SpyCatcher\u2010fusion CNTF into the vitreous body after optic nerve injury leads to prolonged JAK\/STAT3 signaling, increased neuronal survival, and enhanced axon regeneration. This study illustrates a generalizable material system for injectable and sustained delivery of protein therapeutics for neuroprotection and regeneration, with the potential for extension to other chronic diseases and injuries.<\/jats:p>","DOI":"10.1002\/adma.202413957","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T02:31:31Z","timestamp":1733711491000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Clickable, Thermally Responsive Hydrogels Enabled by Recombinant Spider Silk Protein and Spy Chemistry for Sustained Neurotrophin Delivery"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8548-7457","authenticated-orcid":false,"given":"Yue","family":"Li","sequence":"first","affiliation":[{"name":"Department of Chemical and Biological Engineering The Hong Kong University of Science and Technology  Clear Water Bay, Kowloon Hong Kong SAR 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