Mesaconate-Based Polyester Nanoparticles Reveal How Metabolite Isomerism Shapes Polymer Behavior, Macrophage Reprogramming, and Systemic Immunomodulation

Metabolite-based polymer nanoparticles can transform endogenous immunometabolites into intrinsically bioactive materials, yet most platforms have focused on itaconate or soluble metabolite analogs. Mesaconate is a downstream itaconate-derived immunometabolite with distinct metabolic activity, but its potential as an engineerable material building block remains largely unexplored. Here, mesaconic acid was used as a monomer to construct a degradable, cargo-free polyester nanoparticle platform. Poly(itaconate-co-decanediol) (pITA) and poly(mesaconate-co-decanediol) (pMSA) were synthesized using 1,10-decanediol and formulated into nanoparticles. Varying pMSA synthesis conditions generated distinct molecular-weight development, thermal organization, and degradation-associated behavior. Despite comparable particle size, surface charge, and morphology, pITA- and pMSA-derived nanoparticles produced activation-state-dependent macrophage immunomodulation. Under inflammatory stimulation, both nanoparticles modulated activation-associated surface molecules, whereas their transcriptomic responses diverged markedly. pITA-NPs preferentially engaged redox-, metabolic-, and cellular stress-associated programs, while pMSA-NPs exhibited a distinct lysosome-associated, inflammatory, and remodeling transcriptional profile and remained distinguishable from soluble 4-octyl itaconate. In LPS-induced endotoxemia, pMSA-NP treatment broadly modulated systemic cytokine responses, including a pronounced reduction in circulating IL-6, and improved seven-day survival relative to vehicle control. Together, these findings establish mesaconate as a synthesis-tunable polymeric immunometabolite and highlight metabolite-isomer identity and nanoparticle material state as complementary design parameters for cargo-free immunometabolic biomaterials.