In-situ GSH-responsive gas nanogenerator for active NIR-II FL/PA imaging and synergistic restoration the macrophage niche in rheumatoid arthritis

Rheumatoid arthritis (RA) is currently one of the most common systemic autoimmune disorders, with no clinically effective theranostics. Therapeutic manipulation of the gasotransmitter hydrogen sulfide (H 2 S) has exhibited promising potential as an innovative strategy in RA, whereas limited with non-targeting, low solubility, and systemic toxicity. In this work, based on the physicochemical and structural advantages of stimulus-responsive nanotechnology, we develop multifunctional glutathione (GSH)-responsive H 2 S nanogenerators (BDMA NGs), achieving activatable precise second near-infrared fluorescence (NIR-II FL)/photoacoustic (PA) bimodal imaging-guided gas/chemotherapy synergistic therapy. Contributed to the suitable size and excellent biocompatibility, the BDMA NGs accumulate passively in the RA region and then feature a responsive deformation reaction with GSH to release functional small molecules: H 2 S and methotrexate (MTX). The H 2 S undergoes a mineralization process with Ag + ions in situ, resulting in the rapid formation of Ag 2 S to “turn on” the NIR-II FL/PA signals. Remarkably, the effective generation of H 2 S downregulates hypoxia-inducible factor-1 α (HIF-1 α ) and promotes nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, thereby restoring homeostasis in the RA microenvironment and facilitating the reprogramming of pro-inflammatory macrophages (M1) into anti-inflammatory phenotype (M2). Moreover, the controlled release of MTX, clinically approved drug for RA, synergistically promotes repolarization to further suppress local inflammation. Overall, the H 2 S-based nanogenerators BDMA NGs present a sophisticated and versatile strategy for implementing stimuli-responsive imaging and M1-to-M2 repolarization, demonstrating significant potential in the theranostics of RA and clinical transformation.