Dexamethasone palmitate-loaded nanodiscs target inflamed joints and suppress rheumatoid arthritis.

Rheumatoid arthritis (RA) is driven by persistent joint inflammation and dysregulated adaptive immune responses, highlighting the need for drug delivery strategies that can concentrate immunomodulatory therapy at inflamed joints and disease-associated lymphatic tissues. Here, we formulated dexamethasone palmitate-loaded synthetic high-density lipoprotein nanodiscs (DXP-NDs) as a biomimetic nanodelivery platform for subcutaneous administration and inflammation-directed delivery. DXP-NDs exhibited excellent encapsulation efficiency (95.8% ± 2.4%) and maintained their ~10 nm size for 60 days during storage either at 4 °C or 37 °C. DXP-NDs downregulated MHC-II and costimulatory molecules (CD40/CD80/CD86) on bone marrow-derived dendritic cells (BMDCs) in vitro. In the absence of a strong antigenic signal, this costimulatory blockade significantly promoted regulatory T cell (Treg) differentiation. In contrast, upon strong antigen exposure, DXP-NDs aborted productive T-cell activation, suppressing proliferation and locking T cells in an unactivated, anergic state. Following subcutaneous administration, DiR-labeled nanodiscs selectively accumulated in inflamed joints in both zymosan-induced arthritis and collagen-induced arthritis models, with joint fluorescence correlating strongly with clinical paw scores. In a murine model of zymosan-induced arthritis, DXP-NDs alleviated inflammatory joint swelling and reduced regional Th1 frequencies. In a murine model of collagen-induced arthritis, DXP-ND therapy arrested clinical disease progression and reduced systemic IL-1β levels, with additional evidence of immune remodeling in draining lymph nodes. T-cell analysis revealed reduced Th1 and Th17 frequencies, decreased effector memory T-cell populations, and increased regulatory T-cell frequencies after extended treatment. Overall, these studies demonstrate that DXP-NDs traffic to inflamed arthritic joints and lymphatic tissues after subcutaneous administration and promote coordinated anti-inflammatory and immunoregulatory effects that attenuate joint inflammation and limit disease progression in murine arthritis models.