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However, current interventions lack effective measures that precisely respond to and modulate the dynamic changes in the microenvironment. Herein, a biomaterial\u2010driven platform based on covalent conjugation and enzyme\u2010responsive release, enabling the spatiotemporally controlled delivery of regenerative and immunomodulatory factors, is developed. Following tissue injury, the early\u2010phase protease thrombin and the delayed\u2010phase matrix metalloproteinase\u20102 (MMP2) serve as endogenous triggers that correspond to distinct stages of the microenvironmental evolution. By site\u2010specific covalent conjugation via Sortase A (SrtA)\u2010mediated transpeptidation to intraluminal aligned fibers, combined with outer encapsulation within T\u2010HA (thrombin\u2010responsive cleavable hyaluronic acid gel), it is discovered that sequential delivery (CNTF\/FGF2 followed by IL\u20104) significantly enhances spinal cord injury (SCI) recovery compared to reverse sequencing (IL\u20104 followed by CNTF\/FGF2). Likewise, SrtA\u2010mediated protein conjugation to HA demonstrates that FGF2 delivery preceding IL\u20104 resulted in superior cardiac functional restoration in the myocardial infarction (MI) model. This spatiotemporally system optimizes the critical therapeutic window for inflammation and tissue remodeling after injury, offering a versatile paradigm for addressing the challenges posed by the dynamic nature of injured tissues.<\/jats:p>","DOI":"10.1002\/adma.202512554","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T13:48:18Z","timestamp":1758548898000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Spatiotemporally Engineered Protein Delivery via Integrated Covalent Coupling and Pathological Triggers for Precision Microenvironment Reprogramming in Tissue Injury Repair"],"prefix":"10.1002","volume":"38","author":[{"given":"Rui","family":"Quan","sequence":"first","affiliation":[{"name":"Laboratory of Integrative Physiology Institute of Genetics and Developmental Biology Chinese Academy of Sciences  Beijing 100101 China"},{"name":"University of Chinese Academy of Sciences  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