Buffering cellular stress during mRNA delivery enables immunoregulatory Interleukin-2 therapy.

Messenger RNA (mRNA) therapeutics enable in situ production of immunoregulatory proteins. However, cellular stress induced during delivery remains an underappreciated yet critical determinant of immune outcomes. Strategies to mitigate this stress have so far been limited. Here, we harnessed the intrinsic antioxidant and anti-inflammatory activities of curcumin by conjugating it to the cationic polymer block via pH-responsive boronate ester bonds, yielding stress-buffered mRNA nanocarriers that mitigate delivery-induced cellular perturbations. The nanocarriers remain stable in serum and enable efficient cytosolic mRNA release while reducing reactive oxygen species, suppressing stress-induced cytokine expression and avoiding activation-associated immune bias. Systemic delivery of interleukin-2 (IL-2) mRNA with these nanocarriers selectively expanded regulatory T cells, spared effector T-cell activation, and reversed established colitis in mice. In contrast, delivery with conventional carriers induced cellular stress, blunted the anti-inflammatory effects of IL-2 and failed to relieve the disease. These findings establish stress buffering as a strategy to correct the delivery-induced immune bias and enable context-specific mRNA immunotherapies.