Triangular-shaped homologous heterostructure as photocatalytic H2S scavenger and macrophage modulator for rheumatoid arthritis therapy

Rheumatoid arthritis (RA) is a chronic arthropathy causing cartilage destruction, bone erosion, and even disability. Although some advances in RA treatment have been made based on inflammatory cytokine inhibition, long-term treatment and drug effect have been restrained by severe side effects. Herein, we developed a resveratrol (RSV)-loaded Ag/Ag₂S triangular-shaped homologous heterostructure with polyethylene glycol/folic acid (PEG/FA) modification (Ag/Ag₂S-PEG-FA/RSV NTs) to simultaneously suppress inflammatory cytokine over-expression through photocatalytic H₂S scavenging and macrophage polarization stimulation. On one hand, the over-expressed H₂S, which acted as a pro-inflammatory mediator to activate the MAPK/ICAM-1 pathway and exacerbate inflammation, was eliminated through photocatalysis. The homologous Ag and Ag₂S of the heterostructure enhanced electron separation and transfer by acting as a charge acceptor and electron generator, respectively, which restrained electron/hole recombination and promoted photocatalysis efficiency. Additionally, the intrinsic superoxide dismutase (SOD) and catalase (CAT) activity of Ag decomposed the reactive oxygen species (ROS) over-expressed in the RA microenvironment, which supplied O₂ for the photocatalytic H₂S scavenging progress. On the other hand, RSV, a natural product with anti-inflammatory activity, could be delivered to the inflammatory joint by the targeting effect of PEG-FA, thus inhibiting the IκB/NF-κB pro-inflammatory pathway to induce macrophage interconversion balance from M1 to M2. As expected, the Ag/Ag₂S-PEG-FA/RSV NTs exhibited H₂S scavenging capacity and modulated macrophage polarization to reduce the inflammatory cytokine level and halt RA progression in vitro and in vivo. Overall, this study revealed a therapeutic strategy with high efficacy, which opens broad prospects for RA treatment.