Microenvironment-Responsive Nanoparticles Enhance Rheumatoid Arthritis Treatment by Inducing Apoptosis in Inflammatory Macrophages and Fibroblast-like Synoviocytes.

Rheumatoid arthritis (RA) is a progressive autoimmune disease primarily characterized by persistent synovial inflammation and progressive bone erosion. Due to the complexity of its pathological microenvironment, pharmacological treatment of RA is often limited. This is primarily attributed to the fact that activated macrophages in the RA microenvironment secrete large amounts of pro-inflammatory cytokines, which further activate fibroblast-like synoviocytes (FLS), promoting a hypoxic synovial microenvironment and the release of inflammatory mediators. Inducing apoptosis in these inflammatory cells to mitigate inflammatory responses represents a potential therapeutic strategy for RA. Here, we developed microenvironment-responsive nanoparticles, ATKP-HA/CuS@Cel. Hyaluronic acid (HA) was first used to modify celastrol (Cel)-loaded octahedral copper sulfide nanoparticles (CuS NPs), forming HA/CuS@Cel NPs. Then, alendronate sodium (ALN), a potent osteoclast inhibitor, was conjugated to NH2-PEG-thioketal (TK)-COOH to obtain ALN-TK-PEG (ATKP). Self-assembly of ATKP onto HA/CuS@Cel resulted in the final ATKP-HA/CuS@Cel NPs. In vitro, this formulation enabled the release of Cel and ALN in response to reactive oxygen species, significantly inducing apoptosis of inflammatory macrophages and FLS. In vivo, ATKP-HA/CuS@Cel effectively accumulated at inflamed joint sites and markedly alleviated bone destruction and inflammatory responses in collagen-induced arthritis rats. Overall, our findings provided an innovative delivery strategy that enhanced RA therapeutic efficacy by inhibiting the abundance of various inflammatory cells through microenvironment-driven drug release.