Polypyrrole-ferric phosphate-methotrexate nanoparticles enhance apoptosis/ferroptosis of M1 macrophages via autophagy blockage for rheumatoid arthritis treatment

Rheumatoid arthritis (RA) is an inflammatory disease that progresses from synovial inflammation to cartilage and bone destruction. Eliminating pro-inflammatory M1 macrophages is a promising strategy for RA treatment, but is impeded by cytoprotective autophagy. Herein, we report an effective autophagy blockage-promoted apoptosis/ferroptosis strategy using multifunctional ferric phosphate-decorated, methotrexate-loaded polypyrrole nanoparticles (PPy-FePi-MTX NPs) to achieve enhanced RA treatment effects. When injected into the knee joints of a collagen-induced DBA/1J mouse model of RA, the payloads on PPy NPs are released under the stimulation of an inflammatory microenvironment. The released MTX can directly induce M1 macrophage apoptosis. Upon near-infrared laser irradiation, the photothermal effect of PPy NPs further promotes cellular apoptosis. In addition, Fe³⁺ reacts with intracellular over-expressed glutathione to form Fe²⁺, which can convert hydrogen peroxide into toxic hydroxyl radicals. This redox process could deplete glutathione, inactivate glutathione peroxidase 4, and cause lipid peroxidation accumulation, resulting in ferroptosis of inflammatory M1 macrophages. Furthermore, PO₄^3- disrupts the normal function of lysosomes by pH disturbance, disabling the cytoprotective autophagy of M1 macrophages for enhanced anti-RA effects. This work develops multifunctional PPy NPs for RA treatment through effective elimination of pro-inflammatory M1 macrophage.