Polymer-modified DNA hydrogels for living mitochondria and nanozyme delivery in the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to joint deformities and functional impairments. Traditional treatment approaches, such as nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and molecular targeted therapies, often fail to simultaneously achieve efficient inflammation relief and cartilage tissue repair. DNA hydrogels, derived from nucleic acid nanotechnology, have demonstrated potential in RA therapy due to their programmability, high biocompatibility, and tunable degradation properties. However, their application is still hindered by challenges including high synthesis costs, immunogenicity risks, and uncontrolled degradation rates. To address these limitations, this study proposes a dual-action strategy involving a polymer-modified DNA hydrogel co-delivering nanozymes and living mitochondria to overcome the constraints of traditional therapies and comprehensively optimize RA treatment outcomes. The incorporation of functionalized polymers significantly reduces synthesis costs and immunogenicity while fine-tuning the degradation rate of the hydrogel, enabling sustained support during bone and cartilage repair. The hydrogel is loaded with Prussian blue nanozymes to scavenge excessive reactive oxygen species (ROS) within the RA microenvironment, alleviating inflammation, and facilitates intracellular delivery of living mitochondria to inhibit ROS production at its source, promoting tissue repair. By integrating endogenous ROS reduction with exogenous ROS clearance, this strategy markedly enhances therapeutic efficacy, offering a novel approach for precise RA treatment and advancing the clinical translation of biomaterials. The graphical abstract illustrates the design and synthesis of a polymer-modified DNA hydrogel co-loaded with Prussian blue nanozymes and functional, healthy mitochondria. This composite hydrogel effectively targets reactive oxygen species (ROS) in the rheumatoid arthritis (RA) microenvironment, reducing inflammation, while mitochondrial transfer helps restore cellular energy metabolism and decrease endogenous ROS production. Both in vitro and in vivo studies highlight its efficacy in enhancing chondrocyte proliferation and differentiation, alleviating RA symptoms, and promoting joint tissue repair. • Dual-action strategy combining DNA hydrogel, nanozymes, and mitochondria for enhanced RA treatment and tissue repair. • Functionalized polymers reduce DNA hydrogel synthesis costs and immunogenicity while optimizing degradation rate. • Integrated ROS regulation improves RA treatment by reducing ROS and promoting inflammation resolution and regeneration.