A multifunctional liposomal polydopamine nanoparticle (MPM@Lipo) was developed to synergistically combine chemotherapy, photothermal therapy (PTT), and oxygen enrichment for the treatment of rheumatoid arthritis (RA). MPM@Lipo was designed to target inflammatory joints, scavenge reactive oxygen species (ROS), and alleviate hypoxia, thereby promoting the transition of M1 macrophages to M2 phenotype. The nanoparticle could accumulate at inflammatory joints, inhibit inflammatory factor production, and protect cartilage, effectively alleviating RA progression in a rat adjuvant-induced arthritis model. Upon laser irradiation, MPM@Lipo elevated temperature, destroyed inflammatory cells, and accelerated methotrexate (MTX) and oxygen production, leading to improved RA treatment outcomes. The nanoparticle's synergistic effects of chemotherapy, PTT, and oxygen enrichment provided a promising strategy for RA treatment. MPM@Lipo was synthesized by first forming polydopamine (PDA) nanoparticles under alkaline conditions, loading MTX onto PDA, and then coating the nanoparticles with a MnO₂ layer. The PDA was then coated with temperature-sensitive liposomes to form MPM@Lipo. The nanoparticle exhibited good biocompatibility, with minimal hemolysis and high drug loading efficiency. In vitro studies showed that MPM@Lipo could release MTX in response to laser irradiation and hydrogen peroxide (H₂O₂), and it had strong photothermal properties, with a photothermal conversion efficiency of approximately 36.43%. The nanoparticle could decompose H₂O₂ and generate oxygen, which helped alleviate hypoxia in RA joints. In vitro and in vivo studies demonstrated that MPM@Lipo could effectively inhibit the proliferation and migration of RA fibroblast-like synoviocytes (RA-FLSs) and macrophages, reduce the production of inflammatory factors, and promote the transition of macrophages from M1 to M2 phenotype. The nanoparticle also showed good pharmacokinetic properties, with prolonged circulation time and enhanced accumulation in inflamed joints. In vivo studies using a rat adjuvant-induced arthritis model showed that MPM@Lipo significantly reduced joint swelling and improved joint function, with minimal toxicity to normal cells. The results indicated that MPM@Lipo has great potential as a multifunctional nanomedicine for the treatment of RA.A multifunctional liposomal polydopamine nanoparticle (MPM@Lipo) was developed to synergistically combine chemotherapy, photothermal therapy (PTT), and oxygen enrichment for the treatment of rheumatoid arthritis (RA). MPM@Lipo was designed to target inflammatory joints, scavenge reactive oxygen species (ROS), and alleviate hypoxia, thereby promoting the transition of M1 macrophages to M2 phenotype. The nanoparticle could accumulate at inflammatory joints, inhibit inflammatory factor production, and protect cartilage, effectively alleviating RA progression in a rat adjuvant-induced arthritis model. Upon laser irradiation, MPM@Lipo elevated temperature, destroyed inflammatory cells, and accelerated methotrexate (MTX) and oxygen production, leading to improved RA treatment outcomes. The nanoparticle's synergistic effects of chemotherapy, PTT, and oxygen enrichment provided a promising strategy for RA treatment. MPM@Lipo was synthesized by first forming polydopamine (PDA) nanoparticles under alkaline conditions, loading MTX onto PDA, and then coating the nanoparticles with a MnO₂ layer. The PDA was then coated with temperature-sensitive liposomes to form MPM@Lipo. The nanoparticle exhibited good biocompatibility, with minimal hemolysis and high drug loading efficiency. In vitro studies showed that MPM@Lipo could release MTX in response to laser irradiation and hydrogen peroxide (H₂O₂), and it had strong photothermal properties, with a photothermal conversion efficiency of approximately 36.43%. The nanoparticle could decompose H₂O₂ and generate oxygen, which helped alleviate hypoxia in RA joints. In vitro and in vivo studies demonstrated that MPM@Lipo could effectively inhibit the proliferation and migration of RA fibroblast-like synoviocytes (RA-FLSs) and macrophages, reduce the production of inflammatory factors, and promote the transition of macrophages from M1 to M2 phenotype. The nanoparticle also showed good pharmacokinetic properties, with prolonged circulation time and enhanced accumulation in inflamed joints. In vivo studies using a rat adjuvant-induced arthritis model showed that MPM@Lipo significantly reduced joint swelling and improved joint function, with minimal toxicity to normal cells. The results indicated that MPM@Lipo has great potential as a multifunctional nanomedicine for the treatment of RA.