Modulation of innate and adaptive immunity by pH-responsive nanozyme-like nanoparticles with high mobility for rheumatoid arthritis alleviation

Rheumatoid arthritis (RA) is driven by the breakdown of immune tolerance, arising from the coordinated actions of synovial inflammation, oxidative stress, and dysregulated cytokine production. To address this challenge, we report pH-responsive core-shell nanoparticles composed of a CaO 2 core and a Ce ion-tannic acid phenolic network shell to restore immune tolerance by reprogramming innate and adaptive immune responses. Under acidic conditions, the nanoparticles undergo structural disassembly, releasing catalytic Ce ions and bioactive Ca 2+ . Through the Ce 3+ /Ce 4+ redox cycle, the nanoparticles efficiently scavenge reactive oxygen species and enable sustained O 2 generation, while O 2 release enhances nanoparticle motility. By alleviating oxidative stress and hypoxia, these nanoparticles restore mitochondrial structure and function in macrophages, promoting anti-inflammatory M2 polarization. Concurrently, improved redox and oxygenation states in dendritic cells suppress glycolysis and inflammatory signaling, resulting in attenuated activation, reduced antigen presentation, and the induction of a tolerogenic phenotype that favors regulatory T cell differentiation. Consequently, immune tolerance is reestablished, leading to effective attenuation of synovitis and, in synergy with released Ca 2+ , significant protection against articular bone and cartilage destruction in a RA mouse model. This work highlights immune metabolic reprogramming as a nanomaterial enabled strategy for durable and comprehensive RA alleviation.