Coupling Mitochondrial Homeostasis to Oxi‐Inflamm‐Aging Network Disruption via Peptide‐Functionalized Nanocomposite Hydrogel for Osteoarthritis Intervention

Abstract

ABSTRACT Osteoarthritis(OA) is an age‐related degenerative joint disease, and the absence of clinically effective therapy places a substantial burden on global health. The crosstalk among oxidation, inflammation, and aging (oxi‐inflamm‐aging) disrupts chondrocytes homeostasis, serving as a critical driver in OA initiation and progression. Here, we developed a mitochondria‐centered therapeutic strategy aimed at concomitantly disrupting the pathogenic oxi‐inflamm‐aging network. This strategy emphasized a novel chimeric peptide (MW) designed by integrating the mitochondrial protective MOTS‐s and cartilage‐targeting WYRGRL. To enhance therapeutic delivery and efficacy, the bifunctional chimeric peptide MW is immobilized onto GeSe nanosheets, which are then embedded within a multifunctional responsive hydrogel composed of HA‐MAL, MMP13‐sensitive peptide, and PF127 (HMP), forming the peptide‐functionalized nanocomposite hydrogel (MW@GeSe@HMP). This engineered nanocomposite hydrogel not only exhibited efficient enzyme‐mimicking mimetic properties to scavenge harmful oxygen radicals, but also enabled MMP‐responsive targeted release in chondrocytes. Subsequent biological experiments revealed that MW@GeSe@HMP effectively disrupted the oxi‐inflamm‐aging network by modulating mitochondrial function, thereby maintaining chondrocyte homeostasis. Mechanistically, MW@GeSe@HMP protected chondrocytes via hindering cGAS/STING signaling. The nanocomposite hydrogel also significantly suppressed cartilage damage and matrix degradation, effectively alleviating OA progression in a rat OA model. In conclusion, this study developed a nanocomposite hydrogel integrating bioactive peptides and two‐dimensional nanoenzyme, providing a prospective therapeutic strategy and potential target for OA treatment by regulating oxi‐inflamm‐aging integrative network.