Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint hypoxia and synovial cell proliferation. Therefore, relieving hypoxia and removing synovial cells will be a new direction in the treatment of RA. Vasoactive intestinal peptide-loaded upconversion nanoparticles (UCNPs)@SiO2@Pt@CeO2 (V-USPC) were used for in situ oxygen (O2) production/photothermal/photodynamic treatment of RA. On the one hand, under the irradiation of NIR laser, the optical transition of UCNPs triggers CeO2 to form electron hole pairs which catalyze H2O to produce reactive oxygen species to achieve photodynamic therapy (PDT) which inhibit the proliferation of fibroblast-like synovial (FLS) cells. On the other hand, Pt-mediated photothermal therapy also has a certain effect on the removal of proliferative FLS cells. In addition, the catalase activity of CeO2 can catalyze the high level of H2O2 in hypoxia environment to achieve in situ O2 production which can alleviate hypoxia and resist angiogenesis. It is worth noting that the RA was improved by the synergistic action of PDT and PTT, and the generation of oxygen can alleviate RA hypoxia, which is a means to improve PDT. Therefore, the V-USPC NPs shows great potential in improving the therapeutic effect of RA.