Pathological fibrosis is a chronic disease, characterized by excessive extracellular matrix deposition, that remains a significant global health challenge. Despite its prevalence, current antifibrotic therapies are limited due to the complex interplay and signaling of profibrotic macrophages and fibroblast cells that underlies fibrotic tissue microenvironments. This study investigates a novel approach to combat fibrosis, harnessing the antifibrotic properties of the endogenous metabolite itaconate (IA) to target the pathological activation of the macrophage-fibroblast axis in fibrotic disease. To achieve therapeutic delivery relevant to the chronic nature of fibrotic conditions, we incorporated IA into the backbone of biodegradable polyester polymers, poly(dodecyl itaconate) (poly[IA-DoD]), capable of long-term localized release of IA. Degradation characterization of poly(IA-DoD) revealed that IA, as well as water-soluble IA-containing oligomeric groups, is released in a sustained manner. Treatment of murine bone marrow-derived macrophages and human dermal fibroblasts demonstrated that the degradation products of poly(IA-DoD) effectively modulated profibrotic behavior. Macrophages exposed to the degradation products exhibited reduced profibrotic responses, while fibroblasts showed decreased proliferation and myofibroblast α-smooth muscle actin expression. These findings suggest that poly(IA-DoD) has the potential to disrupt the fibrotic cycle by targeting key cellular players. This polymer-based delivery system offers a promising strategy for the treatment of fibrotic diseases.

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