Double Cross‐Linked Hydrogel for Intra‐articular Injection as Modality for Macrophages Metabolic Reprogramming and Therapy of Rheumatoid Arthritis

Abstract Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with abnormalities of the immune system. Recently, the metabolic disorder of immune cells and imbalance within their microenvironment are delineated as key factors triggering the initiation and progression of RA. Therefore, in the present study, injectable hydrogel (hereinafter referred to as siHPTs@ZA hydrogel) assembled through Zn²⁺‐mediated ionic cross‐linking of alginate further cross‐linked with hyperbranched poly(β‐amino ester) loaded with TNF‐α siRNA. The resulting siHPTs@ZA hydrogel is successfully employed to induce metabolic reprogramming of macrophages toward regulating the ratio of M1/M2 polarization. In the hypoxic microenvironment, administration led to downregulation of the GLUT1 expression consequently suppressing pro‐inflammatory M1 macrophages relying primarily on glycolysis. In addition, exposure to an acidic environment triggered the degradation of siHPTs@ZA hydrogel resulting in the release of Zn²⁺ that activated expression of PPARγ accelerating fatty acid oxidation, subsequently inducing anti‐inflammatory M2 macrophage polarization. Taken together, under a hypoxic microenvironment, the presented injectable hydrogel is able to induce reprogramming of immunometabolism, thus being a promising platform for next‐generation, highly efficient treatment of RA.