LAUSR

To restore the disordered endogenous gas levels is an efficient alternative for the treatment of rheumatoid arthritis (RA). Both insufficient hydrogen sulfide (H2S) and excessive nitric oxide (NO) contribute to synovial inflammation. Herein, a new block polymer PEG10‐b‐PNAPA30‐b‐PEG10 composed of an NO‐responsive monomer and a cysteine‐triggered H2S donor, which can simultaneously scavenge NO and release therapeutic H2S 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‐κB signaling pathway. It leads to the polarization of macrophages from M1 to M2 phenotype. Moreover, the released H2S 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 H2S release and NO depletion. This work provides new insight into the synergistic treatment of RA and endogenous gas‐related diseases.