Coordinating interleukin-2 encoding circRNA with immunomodulatory lipid nanoparticles to potentiate cancer immunotherapy

作者：Kai Yang, Bing Bai, Xiaomei Li, Wei Rou, Cheng Huang, Meixin Lu, Xueyan Zhang, Chunbo Dong, Shaolong Qi, Zhida Liu, Guocan Yu · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.adn7256 · 被引用次数：25 · 研究领域：Circular RNAs in diseases、Immune Cell Function and Interaction、RNA Interference and Gene Delivery

Interleukin-2 (IL-2) is a cytokine vital for CD8 + T cell activation and proliferation, holding great potential for cancer immunotherapy. Nevertheless, inherent shortcomings of short half-life, activation of regulatory T (T reg ) cells, and systemic toxicity limit its application. To tackle these, a circular RNA (cRNA)–based IL-2 therapy using immunomodulatory lipid nanoparticles [ursodeoxycholic acid lipid nanoparticles (ULNPs)] and sustained-release hydrogel was developed. Fusing fragment crystallizable (Fc) region into IL-2 and encoding this fusion protein IL-2-Fc (IL-2F) in cRNA (cRNA IL-2F ) greatly extend the half-life. ULNPs containing ursodeoxycholic acid, a transforming growth factor-β1 inhibitor, suppress the function of T reg cells. Consequently, the ULNPs-cRNA IL-2F formulation promotes CD8 + T cells and suppresses T reg cells, increasing the CD8 + /T reg ratio for effective immunotherapy. Furthermore, a locally administrated hydrogel loading with ULNPs-cRNA IL-2F sustains the release, enhancing efficacy and reducing toxicity. This innovative approach achieves remarkable tumor inhibition in both melanoma and orthotopic glioma models with or without surgery, offering a promising future for cancer immunotherapy.