Pathology‐Responsive Self‐Assembling Hydrogel Enabling Spatiotemporally Controlled Exosome Release and Redox Regulation for Intervertebral Disc Regeneration

Abstract

ABSTRACT Intervertebral disc degeneration (IVDD) arises from disrupted metabolism and redox imbalance, severely impairing nucleus pulposus (NP) cells’ ability to repair the extracellular matrix (ECM). The early stage of IVDD is marked by excessive oxidative stress, lipid peroxidation, iron dysregulation and sustained catabolic enzyme activity, while late‐stage cellular aging ultimately renders NP cells highly susceptible to iron‐dependent cell death. To address these stage‐specific challenges, we developed a pathology‐adaptive self‐assembling hydrogel that exploits dynamically varying catabolic enzyme activity to trigger on‐demand delivery of antioxidant molecules and bioactive extracellular vesicles. Upon recognition of pathologically elevated MMP13, the hydrogel undergoes site‐specific structural disruption, thereby enabling spatiotemporally controlled exosome release. The hydrogel complex stabilizes redox balance by boosting intracellular glutathione, mitigating lipid peroxidation and restoring iron homeostasis. Furthermore, it activates PI3K‐Akt signaling and reinstates key anti‐ferroptosis proteins. Simultaneously, it promotes the synthesis of proteoglycans and type II collagen, collectively rebuilding the ECM niche. The combined effect of restored redox balance and regenerative signaling leads to significant structural and functional recovery of the damaged disc, as strongly evidenced in vivo animal studies. Overall, this spatiotemporal‐adaptive platform establishes a multifaceted strategy for regenerative engineering, offering a promising option for complex degenerative diseases.