Abstract

Abstract The ability to deliver protein therapeutics in a minimally invasive, safe, and sustained manner, without resorting to viral delivery systems, will be crucial for treating a wide range of chronic injuries and diseases. Among these challenges, achieving axon regeneration and functional recovery post‐injury 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‐gel transition at an elevated temperature (37 °C) following brief sonication. This thermally triggered gelation confers injectability to the system. Leveraging SpyTag/SpyCatcher chemistry, the hydrogel, composed of SpyTag‐fusion spidroin, can be functionalized with diverse SpyCatcher‐fusion bioactive motifs, such as neurotrophic factors (e.g., ciliary neurotrophic factor) and cell‐binding ligands (e.g., laminin), rendering it well‐suited for neuronal culturing. More importantly, the intravitreous injection of the protein materials decorated with SpyCatcher‐fusion 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.