MMP-responsive hydrogel: a new approach for tissue repair and regeneration

• The crucial design principles of MMP-responsive hydrogels, including substrate composition, polymer networks, synthesis methods and drug loading strategies are systematically discussed. • Various hydrogel forms and their targeted applications in wound healing, bone/cartilage repair, myocardial regeneration, and neural repair are introduced • Key challenges faced by MMP-responsive hydrogels and future directions are highlighted. Tissue injury can lead to structural and functional abnormalities, severely impacting health-related quality of life. Due to the complex dynamics of the tissue injury microenvironment, traditional hydrogels struggle to achieve real-time drug release regulation tailored to disease progression. Given that matrix metalloproteinases (MMPs) exhibit highly specific and significant changes within this microenvironment, MMP-responsive hydrogels have been designed to recognize pathologically overexpressed MMPs, enabling spatiotemporal-controlled drug release and remodeling of the injury microenvironment. Additionally, the three-dimensional network structure of hydrogels not only provides a scaffold for cell migration and proliferation but also effectively fills irregular tissue defects, thus overcoming the mechanical support limitations of nanocarriers. This review systematically summarizes the multi-scale design strategies of MMP-responsive hydrogels, including their composition designs, synthetic methods, and drug loading strategies, while delving into their mechanisms of action in wound healing, bone/cartilage repair, myocardial regeneration, and neural repair. Furthermore, we analyze the current opportunities and challenges in clinical translation, providing insights for developing next-generation intelligent hydrogels.