Hydrolysis of 2D Nanosheets Reverses Rheumatoid Arthritis Through Anti‐Inflammation and Osteogenesis

Abstract Rheumatoid arthritis (RA) is a kind of inflammation homeostasis disorder that dysfunctions the joints. Clinically, medications against RA focus simply on mitigating the focal inflammation, without considering pro‐osteogenesis re‐modeling of the bone microenvironment. In the present work, 2D layered calcium disilicide nanoparticles (CSNs) are fabricated by facile aqueous exfoliation. The hydrolysis of CSNs produces anti‐oxidative H₂, alkaline Ca(OH)₂, and silica. These moieties play significant roles in anti‐oxidation, anti‐inflammation, and pro‐osteogenesis resulting in considerably better RA therapeutic consequences than anti‐inflammation alone. Hydrogen gas is validated to eliminate excessive hydroxyl radicals and regulate macrophage re‐polarization; the generated Ca(OH)₂ can neutralize the acidic microenvironment and inhibit the osteoclast activity; and, the dissolved Ca²⁺ can effectively complex with phosphates to mineralize Ca₃(PO₄)₂, promoting the osteogenesis of the focal joint. The multifunctional performances of CSNs are further confirmed in arthritic mouse and rabbit models, providing an advanced and robust therapeutic strategy against RA with high biocompatibility and clinical transformable promises.