Poly(itaconic acid) Nanoparticles Alleviate Inflammation and Multiorgan Injury in Sepsis by Promoting Nuclear Factor Erythroid 2-Related Factor 2 Nuclear Translocation and Macrophage Reprogramming.

Abstract

Sepsis is a serious syndrome characterized by acute dysfunction of multiple organs, and there is a notable lack of effective preventive strategies and interventions. As a natural anti-inflammatory and antioxidant feedback regulator in the body, itaconic acid can precisely and synergistically modulate anti-inflammatory and antioxidant effects through various mechanisms, providing a metabolic regulation strategy for inflammatory diseases and diseases related to oxidative damage. Previous studies primarily utilized small molecule derivatives of itaconate, such as dimethyl itaconate (DMI) and itaconate 4-octyl ester. However, their in vivo stability and tissue targeting capabilities are often suboptimal, significantly reducing their anti-inflammatory and antioxidant efficacy in disease treatment. Poly itaconic acid (pIA) was synthesized through a one-step polymerization method, and pIA NPs were prepared using nanoprecipitation, effectively addressing the current challenges associated with itaconic acid delivery. Through comprehensive in vitro and in vivo evaluations, the nanoparticles have demonstrated good biocompatibility in the inflammatory microenvironment and can specifically release, thereby enhancing its targeting at the sites of inflammation. In contrast to dimethyl itaconate, pIA NPs exhibited enhanced anti-inflammatory and antioxidant properties, which more effectively safeguard against multi-organ dysfunction caused by sepsis and increase the survival rate in mice. Mechanistic investigations demonstrated that these therapeutic benefits mainly occurred through the facilitation of nuclear factor erythroid 2-related factor 2 nuclear translocation and the reprogramming of macrophages by pIA NPs. Furthermore, the preparation process of the nanoparticles are simple and cost-effective, providing a foundation for the clinical translational application of itaconic acid. STATEMENT OF SIGNIFICANCE: This work innovatively developed a simple, safe esterase-responsive polymer delivery system for itaconic acid, solving defects of complex preparation, poor stability and targeting of conventional systems. It advanced sepsis therapy and macrophage metabolic regulation research. For journal readers, it links nanomedicine, immunometabolism and sepsis treatment, providing valuable insights for researchers in inflammatory diseases and drug delivery.