Cationic microparticles inhibit local sterile inflammation in tissue injuries

Sterile inflammation driven by circulating cell-free nucleic acids (cfNAs) plays a critical role in immune activation across various pathological conditions, including autoimmune diseases and tissue injuries. In this study, we explore the potential of polycation-coated microparticles as localized cfNA scavengers designed to mitigate inflammation without the risk of cellular uptake that could reactivate toll-like receptor (TLR) pathways. Using chemical-induced cell death models, we show that the amount of cfNAs released varies depending on cell type and drug treatment. The cationic microparticles effectively inhibit TLR activation by various cfNA forms, including ssDNA, dsRNA, DNA-antibody complexes, as well as cfNAs derived from dying-cell supernatants and lupus patient plasma. Microparticles coated with polycations such as protamine sulfate and poly-L-lysine blocked cfNA uptake and reduced TLR activation by 40-60% in cell culture models. <i>In vivo</i>, they demonstrated therapeutic efficacy by mitigating acute peritonitis, reducing inflammation in temporomandibular joint (TMJ) dysfunction, and minimizing secondary tissue damage in spinal cord injury. Additionally, we used a microfluidics-based approach to fabricate uniform, biocompatible chitosan microparticles with enhanced cfNA-scavenging capabilities. These findings highlight the potential of polycation-coated microparticles as a localized strategy for mitigating cfNA-driven inflammation and promoting tissue recovery in sterile inflammatory diseases.