A Novel Immune-Modulating Nanodrug Enhances Liver-Targeted mRNA Delivery

Liver-specific delivery of mRNAs encoding key regulatory genes via lipid nanoparticles (LNPs) is promising to restore liver homeostasis and resume liver functions in inflammatory liver diseases. However, inflammation downregulates the global mRNA expression in general as a self-defensive mechanism, e.g., to block viral protein expression, which also reduces the efficiency of therapeutic mRNA delivered to hepatocytes. In addition, ionizable LNPs are immunogenic, which exacerbates inflammation. In this project, we applied a novel immune-modulating telodendrimer (TD) nanodrug (ND) to inhibit inflammation and improve specific mRNA delivery. We tested TD ND in both mouse and human immune cells, liver cell lines, and primary human hepatocytes (PHH) to inhibit endotoxin-induced inflammation. TD ND was able to inhibit both endogenous and LPS-induced inflammation in liver cells, which improved cell proliferation in culture and also significantly enhanced the efficiency of mRNA/LNP delivery both <i>in vitro</i> in human monocytes and PHH. Finally, we demonstrated that TD ND is superior to steroid drugs in inhibiting endotoxin-induced inflammation and sustaining liver function in mice, thereby rebooting the efficacy of liver-targeted LNP mRNA delivery and expression. These findings highlight the potential of TD ND as an effective adjuvant therapy to enhance mRNA delivery for inflammatory disease treatments.