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

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.