Targeting Lymph Nodes for Systemic Immunosuppression Using Cell‐Free‐DNA‐Scavenging And cGAS‐Inhibiting Nanomedicine‐In‐Hydrogel for Rheumatoid Arthritis Immunotherapy

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease with pathogenic inflammation caused partly by excessive cell‐free DNA (cfDNA). Specifically, cfDNA is internalized into immune cells, such as macrophages in lymphoid tissues and joints, and activates pattern recognition receptors, including cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS), resulting in overly strong proinflammation. Here, nanomedicine‐in‐hydrogel (NiH) is reported that co‐delivers cGAS inhibitor RU.521 (RU) and cfDNA‐scavenging cationic nanoparticles (cNPs) to draining lymph nodes (LNs) for systemic immunosuppression in RA therapy. Upon subcutaneous injection, NiH prolongs LN retention of RU and cNPs, which pharmacologically inhibit cGAS and scavenged cfDNA, respectively, to inhibit proinflammation. NiH elicits systemic immunosuppression, repolarizes macrophages, increases fractions of immunosuppressive cells, and decreases fractions of CD4 ⁺ T cells and T helper 17 cells. Such skewed immune milieu allows NiH to significantly inhibit RA progression in collagen‐induced arthritis mice. These studies underscore the great potential of NiH for RA immunotherapy.

Abstract

Nanomedicine‐in‐hydrogel (NiH) that co‐delivers cfDNA‐scavenging cationic nanoparticles and a cyclic guanosine monophosphate–adenosine monophosphate synthase inhibitor to draining lymph nodes can decrease the fractions of systemic CD4 ⁺ T cells and Th17 cells, while increasing systemic immunosuppressive Tregs, MDSCs, as well as M2/M1‐like macrophage ratios. The ability of NiH to elicit systemic immunosuppression and restored immune homeostasis in collagen‐induced arthritis mice suggests that NiH holds the potential to benefit rheumatoid arthritis immunotherapy.