Nitric Oxide Scavenging and Hydrogen Sulfide Production Synergistically Treat Rheumatoid Arthritis

Abstract To restore the disordered endogenous gas levels is an efficient alternative for the treatment of rheumatoid arthritis (RA). Both insufficient hydrogen sulfide (H 2 S) and excessive nitric oxide (NO) contribute to synovial inflammation. Herein, a new block polymer PEG 10 ‐ b ‐PNAPA 30 ‐ b ‐PEG 10 composed of an NO‐responsive monomer and a cysteine‐triggered H 2 S donor, which can simultaneously scavenge NO and release therapeutic H 2 S for RA treatment, is reported. In vitro experiments demonstrate that the polymer exhibits a synergistic effect on suppressing reactive oxygen species levels and pro‐inflammatory cytokine production via NF‐ κ B signaling pathway. It leads to the polarization of macrophages from M1 to M2 phenotype. Moreover, the released H 2 S further restrains NO production by suppressing the expression of iNOS. In vivo experiments with an RA rat model show that the system markedly mitigates the synovial inflammation, osteoporosis, and clinical symptoms of RA rats, which is attributed to the combination therapy of H 2 S release and NO depletion. This work provides new insight into the synergistic treatment of RA and endogenous gas‐related diseases.