ROS-responsive Ganoderma lucidum polysaccharide nanocomposite targeting prosenescent oxidative stress niche for structural and functional diabetic tendon regeneration

Diabetic patients exhibit higher tendon injury incidence, with elevated risks of healing failure and re-rupture than healthy individuals, posing major clinical challenges. Tendon stem/progenitor cells (TSPCs) are crucial for tendon homeostasis maintenance, and their senescence underlies regenerative impairment. In this study, diabetic rat Achilles tendon-derived TSPCs (dTSPCs) were identified to exhibit accelerated cellular senescence and dysfunction. Mechanistically, the excessive activation of the Ras/MAPK axis, which mediates mitochondrial dysregulation and elevated reactive oxygen species (ROS) production, was a key driver of dTSPCs senescence and impaired diabetic tendon regenerative capacity. Accordingly, we developed a nanocomposite hydrogel system loaded with Ganoderma lucidum polysaccharides (GLPs), consists of a ROS-responsive PVA-TSPBA hydrogel encapsulating GLPs@ZIF-8 nanoparticles (GZPT). In vitro, GZPT effectively suppressed Ca²⁺ influx, thereby inhibiting aberrant Ras/MAPK axis activation mediated mitochondrial dysfunction and ROS overproduction, ultimately attenuating dTSPCs senescence and dysfunction. In vivo, GZPT enables sustained and precisely controlled release of GLPs, promoting structural regeneration and functional restoration of diabetic tendon defects by mitigating the prosenescent oxidative stress niche. These findings demonstrate that GZPT effectively enhances the functionality of senescent dTSPCs and facilitates diabetic tendon regeneration, suggesting that GZPT represents a promising clinical strategy for improving tendon structural and functional regeneration in diabetic patients.