Lipid Nanoparticle-Mediated Delivery of Enhanced Costimulation Blockade to Prevent Type 1 Diabetes

Abstract

Abstract Type 1 diabetes (T1D) remains an untreatable autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. Costimulation blockade, blocking the CD28 pathway via CTLA4-Ig, is one promising immunotherapeutic, but recent observations suggest its efficacy is antagonized by inflammatory factors. As antigen presenting cells (APCs) malfunctions and aberrant accumulation of type 1 interferons are associated with T1D, we pose that inhibiting the signaling of inflammatory cytokines via Tofacitinib (Tofa), a JAK inhibitor, would enhance the efficacy of CTLA4-Ig in preventing T1D development. The objective of this study was to design a controlled and localized delivery of Tofa via biocompatible lipid nanoparticles, Nanostructured Lipid Carrier (NLC), and assess the immunomodulatory impact of this strategy. We identified a specific composition of NLC that had negligible toxicity, could be readily taken up by multiple immune cells, and had a favorable Tofa encapsulation efficiency. Live animal imaging confirmed these particles have unique property of accumulating in lymphoid tissues, particularly in spleen, pancreatic and mesenteric lymph nodes when administrated via oral gavage. Ex-vivo, Tofa-NLC rapidly delivered Tofa to mouse APCs preventing their maturation and the release of inflammatory cytokines. Ongoing experiments show that short-term administration of Tofa-NLC via oral gavage at early (3-week-old) or late (10-week-old) stage in disease prone NOD mice promotes a significant reduction of T1D onset. Overall, Tofa-NLC represent a promising strategy to complement CTLA4-Ig and we envision this combined strategy could enhance the efficacy of antigen specific immunotherapy.