pH-responsive nano immunomodulator for rheumatoid arthritis therapy via macrophages pyroptosis inhibiting and...

Current immunosuppressive therapies for rheumatoid arthritis (RA) are limited by substantial side effects, prompting the need for strategies that remodel the disease microenvironment via immunomodulation. RA progression is driven by a self-amplifying cycle fueled by elevated extracellular ATP (eATP), reactive oxygen species (ROS) and local acidosis. To disrupt this pathological loop, we developed an intelligent Ce-MOF@CaCO₃ (Ce-Ca) nano-immunomodulator for RA microenvironment remodeling through a pH-responsive "trigger-regulation-therapy" mechanism. In acidic lesions, the CaCO₃ shell degrades to neutralize pH and release Ca²⁺, enabling in situ mineralization and repair of bone surfaces while restoring the multiple enzyme-mimicking activities of the Ce-MOF core. This enables a "dual-clearance and dual-modulation" strategy: hydrolyzing eATP and scavenging ROS to suppress the P2X7R-NLRP3 axis and inhibit M1 macrophage pyroptosis, while converting ATP to adenosine to activate the cAMP-PKA pathway and drive macrophage repolarization to the anti-inflammatory M2 phenotype. By further rebalancing the Keap1-Nrf2 axis and suppressing MAPK/NF-κB signaling, the nano-immunomodulator achieves synergistic microenvironment remodeling, integrating pyroptosis inhibition, immunomodulation, and osteogenic repair, offering a promising nanotherapeutic strategy for RA treatment.