Layered Double Hydroxide Reshapes the Immune Microenvironment of Rheumatoid Arthritis through Small Mothers against Decapentaplegic 5

Persistent synovitis is a pivotal pathological feature of rheumatoid arthritis (RA). However, the current rheumatoid drugs are accompanied by severe side effects and have limited anti-inflammatory capabilities. In this work, we designed a bioactive material-folic acid modified layered double hydroxides (FA-LDH), aiming at targeting M1 macrophages and modulating macrophage repolarization. The in vitro experiment showed that FA-LDH mitigated the release of proinflammatory cytokines and promoted the expression of M2 macrophage markers. In terms of the action mechanism, FA-LDH modulated the nucleocytoplasmic transport of the small mothers against decapentaplegic 5 (Smad5) protein by adjusting the pH within the immune microenvironment. Subsequently, relying on the interaction between phospho-Smad5 (pSmad5) and p65, the nuclear factor kappa B signaling pathway was down-regulated through inhibiting nuclear transport of p65. Additionally, FA-LDH exhibited excellent targeting capability toward M1 macrophages and strong accumulation capacity in inflamed joints. In vivo experiment showed that FA-LDH could relieve swelling of limbs, reduce the infiltration of inflammatory cells, and protect joint cartilage and subchondral bone structure in collagen-induced arthritis mice. In summary, this work introduces a strategy for utilizing bioactive FA-LDH in the treatment of RA, highlighting the potential of FA-LDH to alleviate inflammation and reshape the immune microenvironment through the pSmad5/p65 axis.