Smart Polymer Nanoparticles: Targeting Macrophages/Fibroblasts and Modulating the Microenvironment for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a systemic autoimmune disease associated with a high disability rate. Its core pathogenesis involves immune dysregulation, characterized notably by the aberrant polarization of macrophages toward the pro-inflammatory M1 phenotype, along with the abnormal proliferation and invasion of fibroblast-like synoviocytes. These interrelated processes collectively contribute to progressive joint destruction. Although traditional drug therapies can alleviate symptoms, they are frequently accompanied by significant side effects and fail to achieve curative outcome. In this context, smart polymer nanoparticles (SPNs) have emerged as a promising platform for rheumatoid arthritis therapy, offering multifunctional capabilities. Here, we provide a comprehensive and timely analysis of the multifaceted therapeutic applications of SPNs in RA. By delivering immunomodulatory agents, smart polymer nanoparticles can rebalance macrophage polarization, promoting M1-to-M2 conversion. Moreover, they effectively suppress the pathological activation of fibroblasts, thereby inhibiting synovial proliferation and bone invasion. Furthermore, these nanoparticles can also disrupt the vicious cycle of disease progression by ameliorating metabolic dysregulation within the joint microenvironment. The challenges for the clinical translation of SPNs in RA therapy are discussed and the possible solutions are proposed. Collectively, SPNs fundamentally intervene in RA pathogenesis through precise targeting and intelligent drug release, enabling a highly effective and low-toxicity strategy.