Injectable Hydrogel-Integrated DNA-Programmed Mitochondrial Engagers Metabolically Rewire Synovial Macrophages for Osteoarthritis Repair

Abstract Mitochondrial dysfunction is a hallmark of synovial macrophages (SMs) in osteoarthritic joints, where it critically disrupts metabolic homeostasis in macrophages to promote pro-inflammatory activation, thereby driving OA-associated inflammation, oxidative stress, and cartilage matrix degradation. Herein, we developed an SM metabolic reprogramming strategy to reverse OA-associated osteochondral damage, emphasizing a supramolecular DNA-programmed mitochondrial engager (SDME) that selectively rejuvenates damaged mitochondria by harnessing the endogenous mitochondrial fusion-dependent repair program. SDME was synthesized through the self-assembly of bivalent cytochrome C-binding aptamer (DNA1) with a guanosine triphosphate (GTP)-releasing aptamer (DNA2). To improve the therapeutic performance of SDMEs in the complex osteoarthritic joint cavity, they were integrated with antioxidant quercetin (Qu) into biomineralized CaCO 3 nanosubstrates (BMRN) and further embedded into injectable gelatin/sodium alginate oxide-based hydrogel matrix (IHD). BMRNs were gradually released from the hydrogels following intraarticular injection and taken up by macrophages to deliver SDMEs and Qu-Ca complexes. By competitively binding Cyt-C on dysfunctional mitochondria, SDMEs bring the organelles into close proximity and synchronically release GTP to activate mitofusin-mediated mitochondrial fusion, which cooperates with Qu-Ca-mediated mitochondrial ROS scavenging to enable robust mitochondrial restoration, thereby metabolically reprograming pro-inflammatory macrophages toward a regenerative phenotype for efficient osteochondral healing. Overall, this study proposes a perspective OA treatment strategy through engager-directed mitochondrial rejuvenation.