Engineered decellularized tendon hydrogel with sustained zinc ion release orchestrates anti-inflammatory microenvironment and functional regeneration in Achilles tendinopathy.

Achilles tendinopathy (AT), a prevalent degenerative tendon pathology characterized by dysregulated inflammatory pathways and compromised tissue healing capacity, necessitates the development of novel therapeutic approaches targeting molecular mechanisms of tendon repair. This study developed a zinc oxide nanoparticle (ZnO NPs)-integrated decellularized Achilles tendon extracellular matrix (DAT) hydrogel (Z-D) for minimally invasive AT treatment. The composite hydrogel exhibits thermosensitivity and enhanced mechanical stability through Zn-mediated crosslinking. biocompatibility assessments revealed that 0.25 % Z-D significantly promoted the proliferation capacity of Tendon-Derived Stem Cells (TDSCs), while simultaneously suppressing the expression of key pro-inflammatory mediators, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Under Z-D treatment, TDSCs exhibited accelerated migration and upregulated tenogenic differentiation markers (scleraxis: SCX; tenomodulin: TNMD). In a rat AT model, Z-D implantation achieved multi-level repair: biomechanical restoration and collagen remodeling recovery. Mechanistically, Zn release concurrently promoted TDSCs differentiation and inflammation resolution. Histological evaluation confirmed tendon structural recovery with minimal adhesion formation, and systematic biosafety assessment revealed no organ toxicity. This dual-functional hydrogel system establishes a paradigm for microenvironment-modulating AT therapy by orchestrating anti-inflammatory signaling and regenerative extracellular matrix reconstruction.