Programmable DNA Hydrogel Provides Suitable Microenvironment for Enhancing TSPCS Therapy in Healing of Tendinopathy

Abstract Tendon stem/progenitor cells (TSPCs) therapy is a promising strategy for enhancing cell matrix and collagen synthesis, and regulating the metabolism of the tendon microenvironment during tendon injury repair. Nevertheless, the barren microenvironment and gliding shear of tendon cause insufficient nutrition supply, damage, and aggregation of injected TSPCs around tendon tissues, which severely hinders their clinical application in tendinopathy. In this study, a TSPCs delivery system is developed by encapsulating TSPCs within a DNA hydrogel (TSPCs‐Gel) as the DNA hydrogel offers an excellent artificial extracellular matrix (ECM) microenvironment by providing nutrition for proliferation and protection against shear forces. This delivery method restricts TSPCs to the tendons, significantly extending their retention time. It is also found that TSPCs‐Gel injections can promote the healing of rat tendinopathy in vivo, where cross‐sectional area and load to failure of injured tendons in rats are significantly improved compared to the free TSPCs treatment group at 8 weeks. Furthermore, the potential healing mechanism of TSPCs‐Gel is investigated by RNA‐sequencing to identify a series of potential gene and signaling pathway targets for further clinical treatment strategies. These findings suggest the potential pathways of using DNA hydrogels as artificial ECMs to promote cell proliferation and protect TSPCs in TSPC therapy.