Itaconate-based hydrogels for immunomodulation and infection control: design strategies, biomedical applications, and translational challenges

Itaconate is a bioactive immunometabolite with anti-inflammatory, antioxidant, and antimicrobial properties. Its unsaturated dicarboxylic structure allows for versatile polymerization and chemical functionalization. These characteristics make it a promising building block for bioactive hydrogels. However, current research on itaconate-based hydrogels is fragmented across immunology, polymer chemistry, and biomedical engineering, with a lack of a unified design framework. In this review, we summarize the biological properties of itaconate and its derivatives relevant to biomaterial design, including immunomodulatory effects and antimicrobial activity. We categorize itaconate-based hydrogels into two main strategies: those directly fabricated from itaconate or its analogues, and those loaded with itaconate or itaconate derivatives such as 4-octyl itaconate (4-OI) and dimethyl itaconate (DMI). We explore the relationships between composition, crosslinking chemistry, responsiveness, biological functions, and therapeutic applications in drug delivery, tissue repair, inflammatory diseases, and anti-infective therapy. We also highlight critical limitations, including insufficient structure-function comparisons, overreliance on small-animal models, limited mechanistic validation, and challenges in manufacturing, stability, biosafety, and clinical translation. This review presents a conceptual framework for the rational design of itaconate-based hydrogels and outlines key priorities for advancing these materials toward clinical translation as bioactive and immunomodulatory hydrogel platforms.