Delivery of Synthetic Interleukin‐22 mRNA to Hepatocytes via Lipid Nanoparticles Alleviates Liver Injury

Abstract Hepatocellular injury, a pivotal contributor to liver diseases, particularly hepatitis, lacks effective pharmacological treatments. Interleukin‐22 (IL‐22), crucial for liver cell survival, shows potential in treating liver diseases by regulating repair and regeneration through signal transducer and activator of transcription 3 (STAT3) activation. However, the short half‐life and off‐target effects limit its clinical applications. To address these issues, lipid nanoparticles are employed to deliver synthetic IL‐22 mRNA (IL‐22/NP) for in situ IL‐22 expression in hepatocytes. The study reveals that IL‐22/NP exhibits liver‐targeted IL‐22 expression, with increased IL‐22 levels detected in the liver as early as 3 h postintravenous injection, lasting up to 96 h. Furthermore, IL‐22/NP activates STAT3 signaling in an autocrine or paracrine manner to upregulate downstream factors Bcl‐xL and CyclinD1, inhibiting hepatocyte apoptosis and promoting cell proliferation. The therapeutic efficacy of IL‐22/NP is demonstrated in both chronic and acute liver injury models, suggesting IL‐22 mRNA delivery as a promising treatment strategy for hepatitis and liver diseases involving hepatocellular injury.