Microparticles synthesized from itaconate polyesters enable metabolite delivery and elicit immunoregulatory outcomes

Metabolites directly influence immune cell function. Consequently, altering metabolite availability can regulate immunity and represents a window of opportunity for therapeutic manipulation. Itaconate (ITA) - a tricarboxylic acid cycle derivative generated intracellularly - has been shown to exert anti-inflammatory effects in models of autoimmunity. However, efficacy is dependent on systemic, frequent, high-dose treatments due to ITA's poor membrane permeability and rapid clearance from circulation. Thus, there is a need for metabolite delivery strategies that overcome these challenges. Here, we synthesized ITA-based polyesters that enable microparticle (MP) assembly entirely from the polymeric metabolite (pITA). Treatment with biocompatible pITA MPs, which hydrolyze to release unmodified ITA, reduced inflammatory cytokine secretion (e.g., IL-6, IL-1β) by both macrophages and dendritic cells. These data suggest MPs effectively deliver metabolite to the intracellular compartment for immunomodulation in an accessible form. Furthermore, pITA MPs inhibited polarization of inflammatory T cells (T_H17) and promoted regulatory T cells (T_reg), linking the effect of MPs on innate signaling to adaptive immunity. In a preclinical mouse model of multiple sclerosis (MS), pITA MPs reduced circulating serum IL-6 - a cytokine that drives inflammation in several autoimmune diseases. Together, this work advances a biomaterials-based strategy that overcomes hurdles to metabolite delivery and expands opportunities for intervention during autoimmunity and inflammation.