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 Zn²⁺-mediated crosslinking. <i>In vitro</i> 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, Zn²⁺ 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.