Injectable exosome-reinforced konjac glucomannan composite hydrogel for repairing cartilage defect: activation of endogenous antioxidant pathways

Enhancing the regeneration of cartilage defects remains a formidable challenge, as the dysregulated microenvironment and its crosstalk with chondrocytes play pivotal roles in impairing regeneration. In this study, we proposed a natural plant polysaccharides-derived injectable hydrogel (Exos@EKM) for adapting to irregular cartilage defects. By encapsulating stem cell-derived exosomes (Exos) into polyphenol modified methacryloylated konjac glucomannan (EKM), this hydrogel exerting a potent biological synergistic effect. First, the hydrogel demonstrates favorable biocompatibility and has the capability to modulate cellular behavior through the delivery of Exos. Additionally, it demonstrates significant chondroprotective effects and reprograms macrophages to the pro-healing state. Furthermore, konjac glucomannan and polyphenols in hydrogel synergistically activate the endogenous antioxidant capacity of chondrocytes through nuclear factor erythroid 2-related factor 2 (NRF2)-dependent pathway, thereby optimizing the biological function of Exos in regulating chondrocyte behavior and maintaining normal cartilage metabolism. In a full-thickness cartilage defect model, in vivo implantation of Exos@EKM hydrogel successfully improved cartilage regeneration and ultimately restoring knee joint functionalities. Overall, this combination of natural konjac glucomannan, polyphenols and Exos has resulted in the promotion the harmony between the microenvironment, chondrocyte and ECM. This study offers a novel approach for designing biomaterials for cartilage tissue engineering.