Spatiotemporally Engineered Protein Delivery via Integrated Covalent Coupling and Pathological Triggers for Precision Microenvironment Reprogramming in Tissue Injury Repair

  • Adv Mater. 2025 Sep 22:e12554. doi: 10.1002/adma.202512554.
Rui Quan  1  2 ,  Xianglin Hou  1 ,  Jing Zhang  3  4 ,  Zhenni Chen  5 ,  Weiyuan Liu  1  2 ,  Bo Guo  1 ,  Chunyang Xu  1 ,  Man Yin  1 ,  Shuaijing Zhao  1  2 ,  Shuyu Han  1  2 ,  Yanyun Yin  1 ,  Bing Chen  1 ,  Zhifeng Xiao  1 ,  Jianwu Dai  1  6 ,  Yannan Zhao  1
Affiliations
  • 1. Laboratory of Integrative Physiology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
  • 2. University of Chinese Academy of Sciences, Beijing, 100101, China.
  • 3. Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China.
  • 4. Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, 100029, China.
  • 5. Zhejiang Chinese Medical University, Zhejiang, 310053, China.
  • 6. Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China.
PMID: 40981608 DOI: 10.1002/adma.202512554
Abstract

Tissue injury presents a complex microenvironment with temporal pathological dynamics, necessitating precision therapeutic strategies. However, current interventions lack effective measures that precisely respond to and modulate the dynamic changes in the microenvironment. Herein, a biomaterial-driven platform based on covalent conjugation and enzyme-responsive release, enabling the spatiotemporally controlled delivery of regenerative and immunomodulatory factors, is developed. Following tissue injury, the early-phase protease Thrombin and the delayed-phase matrix metalloproteinase-2 (MMP2) serve as endogenous triggers that correspond to distinct stages of the microenvironmental evolution. By site-specific covalent conjugation via Sortase A (SrtA)-mediated transpeptidation to intraluminal aligned fibers, combined with outer encapsulation within T-HA (thrombin-responsive cleavable hyaluronic acid gel), it is discovered that sequential delivery (CNTF/FGF2 followed by IL-4) significantly enhances spinal cord injury (SCI) recovery compared to reverse Sequencing (IL-4 followed by CNTF/FGF2). Likewise, SrtA-mediated protein conjugation to HA demonstrates that FGF2 delivery preceding IL-4 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.

Keywords
biomaterials; injury repair; responsive release.
Products