An Implantable Optogenetics‐Engineered Hydrogel for Amelioration of Rheumatoid Arthritis through Light‐Controlled Metabolic Reprogramming of Synovial Macrophages

Rheumatoid arthritis (RA) has always been a therapeutic challenge in clinical due to the lack of effective drug treatments. Inspired by the impact of daily diet on RA, herein we proposed an innovative energy metabolism modulation strategy to reprogram synovial macrophages for RA treatment. An implantable hydrogel, encapsulating with optogenetics-engineered cells, was designed to enable in-situ and on-demand secretion of glucagon-like peptide-1 (GLP-1) through blue light irradiation. GLP-1 in synovium was found to activate GLP-1R/HK2/VDAC1 pathway to upregulate the tricarboxylic acid cycle and oxidative phosphorylation in macrophages. This metabolic reprogramming elicited a phenotypic transition in macrophage polarization, shifting from M0/M1 state to M2 state. Significantly, the GLP-1-mediated approach reduced synovial inflammatory cytokine levels and facilitated tissue repair and bone erosion recovery. These findings reveal the therapeutic potential of GLP-1R/HK2/VDAC1 pathway as a novel target for RA.