Energy-responsive multi-catalytic nanogenerator hydrogels synergistically enhance diabetic tendon-to-bone healing via the ages/RAGE/PIEZO2 axis.

Rotator cuff tears (RCTs) represent a significant clinical challenge with high post-operative re-tear rates, especially in diabetic patients. Through comprehensive bioinformatic analysis of a publicly available transcriptomic dataset (GSE236746), we identified the significant downregulation of the mechanosensitive hub gene PIEZO2 and the aberrant activation of oxidative stress/inflammatory pathways as primary pathological barriers in diabetic patients. This metabolic dysfunction triggers the advanced glycation end products (AGEs)/receptor for AGEs (RAGE) axis, creating a self-amplifying oxidative stress loop that traps macrophages in a persistent pro-inflammatory M1 phenotype and impairs the recruitment of bone/tendon progenitor cells. Addressing these interconnected metabolic and mechanical barriers, we engineered an energy-responsive, multi-catalytic nanocomposite (Au-Pd/BTO, termed APB) integrated into a thermosensitive Pluronic F127 hydrogel (APBF). The APBF platform functions as a "metabolic-electric" dual-regulator: the cascade enzyme mimetic activities (glucose oxidase [GOD]-, superoxide dismutase [SOD]-, and catalase [CAT]-like) of the Au-Pd alloy effectively attenuate the glucose-reactive oxygen species (ROS)-AGEs/RAGE cascade. Thereby resolving the inflammatory niche and promoting M2 macrophage polarization. Simultaneously, piezoelectric Barium Titanate (BTO) nanocrystals generate endogenous electrical signals under physiological mechanical loading to compensate for the intrinsic PIEZO2-mediated mechanosensing deficiency, thereby enhancing angiogenesis, osteogenesis, and chondrogenesis. Systematic in vivo evaluation, including micro-computed tomography (micro-CT) analysis analysis, biomechanical testing, and histological assessment, demonstrated that APBF successfully restores the structural integrity and mechanical strength of the tendon-bone interface (TBI). Based on transcriptomic evidence, this study designed of physiology-matched biomaterials for complex tissue regeneration.