ATP-responsive injectable DNA hybrid hydrogels for regulating the “on-demand release” of fibroblast growth factor 21 cytokines to facilitate muscle regeneration

Effective regeneration of injured skeletal muscle remains a major challenge in clinical medicine. There is an urgent demand for therapeutic strategies capable of achieving precise spatiotemporal control over the muscle repair process. To address this clinical challenge, we propose an ATP-responsive injectable DNA hybrid hydrogel, specifically designed to enable “on-demand release” of cytokines, thereby enhancing muscle regeneration. Through the implementation of rational DNA sequence design and optimized cross-linking methodologies, the three-dimensional network of the hydrogel, which is capable of efficiently encapsulating a diverse range of cytokines known to promote tissue repair and remodeling, was constructed. This hydrogel can respond to the characteristic increases in ATP concentration fluctuations within the local tissue microenvironment, enabling precise control over cytokine release and thereby promoting the proliferation and differentiation of muscle cells. This DNA hydrogel, exhibiting excellent biocompatibility, creates a more favorable and functionally optimized microenvironment that supports and promotes muscle regeneration. This “on-demand release” capability not only enhances therapeutic efficacy but also prevents premature drug release prior to reaching the target site and minimizes off-target drug distribution to non-target tissues, thereby improving both the safety and controllability of regenerative treatments.