(540d) Immunomodulatory Nanoparticles for Modulating Autoimmune Arthritis

Disease-modifying drugs (DMARD) have improved the treatment for autoimmune joint disorders, such as rheumatoid arthritis, but inflammatory disease flares are a common experience. While there are no flare-specific DMARD, current flare treatment focuses on symptomatic management with corticosteroids or oral non-steroidal anti-inflammatory drugs. As ∼80% of flares are short-lived (<3 days), switching DMARD to treat flares is not indicated for most patients due to the inherent risks of side-effects and inadequate responsiveness. Moreover, symptomatic control is ineffective at stemming joint damage and flare recurrence. There is a significant unmet need for durable flare control agents. This work reports the development and application of flare-modulating poly(lactic-co-glycolic acid)-poly(ethylene glycol)-maleimide (PLGA-PEG-MAL)-based nanoparticles conjugated with joint-relevant peptide antigens, aggrecan_70–84 and type 2 bovine collagen_{256–270}. Peptide-conjugated PLGA-PEG-MAL nanoparticles encapsulated calcitriol, which acted as an immunoregulatory agent, and were termed calcitriol-loaded nanoparticles (CLNP). In vitro, CLNP induced phenotypic changes in bone marrow derived DC, reducing the expression of costimulatory and major histocompatibility complex class II molecules, and proinflammatory cytokines. Bulk RNA sequencing of DC showed that CLNP enhanced expression of Ctla4, a gene associated with downregulation of immune responses. The hydrodynamic diameter and low polydispersity index favored proximal lymph node accumulation from the site of injection. In vivo, CLNP accumulated in the proximal lymph nodes after intramuscular injection. Administration of CLNP was not associated with changes in peripheral blood cell numbers or cytokine levels. In the collagen-induced arthritis and SKG mouse models of autoimmune joint disorders, CLNP reduced clinical scores, prevented bone erosion, and preserved cartilage proteoglycan, as assessed by high-resolution microcomputed tomography and histomorphometry analysis. The disease protective effects were associated with increased CTLA-4 expression in joint-localized DC and CD4⁺ T cells but without generalized suppression of T cell-dependent immune response. CLNP may serve as an immunoregulatory adjuvant to treat patients who experience recurrent local flares, potentially in combination with DMARD without generalized immunosuppressive side effects.