Membrane biomimetic nanoenzyme-incorporated hybrid glycyrrhizic acid hydrogel for precise mitochondrial ROS scavenging for osteoarthritis treatment.

Osteoarthritis (OA) is a progressive degenerative disorder which severely threatens the quality of life of older individuals. OA progression is closely related to heightened levels of mitochondrial reactive oxygen species (mtROS). Although nanozymes have a good ROS-scavenging effect, they cannot precisely scavenge mtROS because of the immune rejection of cell membranes, lysosomal escape, and the inability of conventional nanozymes to directly target mitochondria. Dual-target nanozymes were engineered to precisely scavenge mtROS in chondrocytes. We used chondrocyte membrane-camouflaged TPP-modified hollow Prussian blue nanozymes and subsequently encapsulated these nanozymes in a hybrid glycyrrhizic acid hydrogel. The therapeutic efficacy and underlying mechanisms were assessed in vitro and in vivo. The novel nanozymes enhanced cell selectivity, immune evasion capabilities, and mitochondrial targeting. The dual-targeted nanozymes exerted a pronounced therapeutic impact on inflammatory chondrocytes, mitigated mtDNA leakage by precisely scavenging mtROS, dampened cGAS-STING-NF-κB signaling, and enhanced chondrocyte function. The hybrid hydrogels also exhibited improved therapeutic outcomes. We confirmed the beneficial effects of the nanozyme-hydrogel combination on OA progression in mice. The nanozyme-hydrogel combination can reduce precisely scavenge mtROS in chondrocytes, avoiding the leakage of mtDNA and suppressing the cGAS-STING-NF-κB signaling pathway, thereby decreasing inflammatory responses and alleviate OA progression.