<p>Rheumatoid arthritis (RA) is a chronic autoimmune disease that features by the overproliferation of fibroblast-like synoviocytes (FLSs). Rapid proliferation and defective apoptosis of FLSs drive the pathogenesis of RA. However, it lacks effective treatment due to monotherapy strategy, adverse effects of drugs, the heterogeneity of FLSs and so on. Herein, a self-amplifying pH-responsive nanoplatform (Mn/Si-Abe@BSA) is developed to induce cell cycle arrest and apoptosis for RA treatment. By loading abemaciclib (Abe) in the manganese-doped mesoporous silica nanoparticles (Mn-MSNs) and modifying with bovine serum albumin (BSA), the multifunctional nanoplatform is successfully fabricated with carbonic anhydrase (CA)-mimicking activity. The nanoplatform can effectively accumulate in the inflammed joints, after which the nanoplatform is in response to the mild acidic microenvironment to release Mn²⁺ and Abe, enhanced by the hydrogen protons (H⁺) deprived from CA-mimicking catalysis. The released Mn²⁺ induces arginine deprivation that cooperates with Abe to induce cell cycle arrest of FLSs. Moreover, Mn²⁺ catalyzes the generation of toxic hydroxyl radical (·OH) to synergize upregulated p53 to kill abnormal FLSs. In summary, a “dual pronged attack” strategy is proposed by the multifunctional nanoplatform Mn/Si-Abe@BSA with novel enzyme-mimic activities, representing a promising platform for the comprehensive management of RA.</p> Graphical abstract <p></p>