Pre-silencing of TNF-α by targeted siRNA delivery mitigates glucocorticoid resistance of dexamethasone in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, progressive inflammatory autoimmune disease marked by relentless synovial inflammation and joint destruction, for which long-term remission remains challenging. Although dexamethasone (DEX) is commonly employed to rapidly control disease activity, its therapeutic effectiveness is often undermined by the development of glucocorticoid resistance (GCR) and cumulative systemic toxicities. Recent insights suggest that TNF-α-driven inflammation not only perpetuates joint pathology but also sustains a molecular landscape that favors GCR, underscoring an urgent need for therapeutic strategies that jointly target inflammatory signaling and steroid sensitivity. Here, we report a nanomedicine-enabled sequential therapy, in which TNF-α specific siRNA (siTNFα) and DEX are separately encapsulated within macrophage-targeted polymersomes (MTP-T and MTP-D, respectively). Through intravenous administration of MTP-T, followed by the intraperitoneal delivery of MTP-D (designated as MTP-T/D(seq)), this sequential therapy acheives efficient knockdown of TNF-α in inflammatory macrophages, leading to enhanced expression of glucocorticoid receptor (GR), an elevated GRα/GRβ ratio, and a substantial reversal of GCR. This modulation sensitizes macrophages to DEX, enabling rapid and effective suppression of pro-inflammatory mediators while reducing toxicity. Our findings demonstrate that our sequential therapy in collagen-induced arthritis (CIA) mouse models not only mitigates joint inflammation and mitochondrial dysfunction but also normalizes the M2/M1 macrophage balance, attenuating synovial hyperplasia and cartilage damage as confirmed by molecular and histological analyses. These findings validate a precision-engineered immune microenvironment remodeling strategy that restores glucocorticoid responsiveness and confers potent therapeutic benefits, offering a compelling blueprint for overcoming steroid resistance in RA.