Treating rheumatoid arthritis using fibroblast-activated protein-α-responsive micelles through a cascade control program.

Rheumatoid arthritis (RA), a chronic autoimmune disorder affecting 1% globally, urgently demands advanced therapies to overcome the systemic toxicity and limited efficacy of conventional glucocorticoids like dexamethasone (Dex). In this study, we constructed LMWH-Gly-Pro-ODA/Dex (LGPO/Dex) micelles, which synergistically integrate low molecular weight heparin (LMWH)-mediated active targeting with Gly-Pro-mediated fibroblast-activated protein (FAP)-α-responsive drug release to achieve spatiotemporal precision in RA treatment. The system operates through a three-stage cascade mechanism: (1) targeting the inflamed joints, (2) inflammation-responsive drug release to modulate pathological microenvironments (e.g., normalizing M1/M2 macrophage polarization), and (3) suppression of monocyte recruitment to prevent disease progression. LGPO/Dex micelles showed excellent RA therapeutic effects in the adjuvant-induced arthritis (AIA) model. Joint swelling, serum TNF-α, and nitric oxide (NO) levels in LGPO/Dex-treated rats showed no significant difference from healthy controls (ns) while exhibiting marked improvement over Dex monotherapy (**, P < 0.01). Notably, it also significantly reduced Dex-associated adverse effects. This study confirmed the feasibility of using FAP-α as a therapeutic target for RA and provided a new idea for RA treatment, offering a blueprint for disease-microenvironment-programmed therapeutics.