Polymeric Aggregate‐Embodied Hybrid Nitric‐Oxide‐Scavenging and Sequential Drug‐Releasing Hydrogel for Combinatorial Treatment of Rheumatoid Arthritis

Abstract Selective depletion of overproduced nitric oxide (NO) with nanoscavengers is a promising approach for treating rheumatoid arthritis (RA), preventing both oxidative/nitrosative stress and the upregulation of immune cells. However, its practical applications are limited owing to the minimum time interval between intra‐articular injections and unwanted off‐target NO depletion. Herein, the rational design of an injectable in situ polymeric aggregate‐embodied hybrid NO‐scavenging and sequential drug‐releasing (M‐NO) gel platform for the combinatorial treatment of RA by incorporating a “clickable” NO‐cleavable cross‐linker (DA‐NOCCL) is reported. This network is held together with polymeric aggregates to achieve a self‐healing capability for visco‐supplementation and on‐demand dual drug (both hydrophilic and hydrophobic)‐releasing properties, depending on the NO concentration. Moreover, consecutive NO‐scavenging action reduces pro‐inflammatory cytokine levels in lipopolysaccharides‐stimulated macrophage cell lines in vitro. Finally, the intra‐articularly injected M‐NO gel with anti‐inflammatory dexamethasone significantly alleviates the symptoms of RA, with negligible toxicity, in animal models. It is believed that this novel M‐NO gel platform will provide a guideline for the combinatorial treatment of RA and various NO‐related diseases.