Exosome-loaded methacrylated silk fibroin hydrogel delays intervertebral disc degeneration by DKK2-mediated mitochondrial unfolded protein response

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, but existing therapies fail to halt its progression. Here, we develop an exosome-loaded methacrylated silk fibroin hydrogel (SM@ME) that synergistically activates the mitochondrial unfolded protein response (UPRmt) to combat IVDD. SilkMA hydrogel, optimized for mechanical compatibility with nucleus pulposus (NP) tissue, enables sustained release of Cavin-2-engineered exosomes (M−EXO). RNA sequencing revealed that SM@ME upregulates DKK2, which suppresses the Wnt/β-catenin pathway while activating UPRmt, thereby reducing apoptosis, and senescence in rat and human NP cells. In vivo , SM@ME injection into puncture-induced IVDD rats attenuated histological degeneration. Notably, lentiviral-mediated overexpression of DKK2 in NP tissues resulted in therapeutic effects similar to those of SM@ME treatment. This work suggests that hydrogel-delivered exosomes can modulate UPRmt for IVDD therapy, offering a novel biomaterial strategy for disc regeneration.