Immunomodulatory Nanoparticles Enable Combination Therapies To Enhance Disease Prevention and Flare Control in Rheumatoid Arthritis.

Disease-modifying antirheumatic drugs (DMARDs) have greatly improved the treatment of rheumatoid arthritis (RA), but strategies to prevent disease onset and recurring flares remain limited. While abatacept (CTLA-4 IgG) can delay RA onset and corticosteroids are used for flare control, the benefit is temporary. We report that combining standard-of-care treatments with a locally administered immunomodulatory agent, termed Agg-CLNP, enhances both disease prevention and flare mitigation. Agg-CLNP consists of polymer nanoparticles conjugated with an immunodominant aggrecan peptide and encapsulate calcitriol. These nanoparticles are optimized for uptake by dendritic cells (DC) in lymph nodes proximal to arthritic joints. In vitro, Agg-CLNP suppressed costimulatory molecules and HLA class II (HLA-2) expression and upregulated CTLA-4 in human monocyte-derived DC from healthy and RA donors. In SKG mice, a T cell-driven RA model, Agg-CLNP combined with CTLA-4 IgG synergistically delayed disease onset and reduced severity. In a dexamethasone (Dex) withdrawal flare model, post-Dex Agg-CLNP treatment reduced flare severity and preserved a regulatory phenotype in DC, while suppressing local pathogenic TH17 cells. Next generation RNA sequencing of lymph node DC revealed Ctla4 upregulation and changes in other immunomodulatory genes linked to flare prevention. These findings highlight Agg-CLNP as a potential therapeutic strategy to address critical unmet needs in RA management.