Huan Bao, PhD
Researchers in the UVA Department of Molecular Physiology and Biological Physics have unraveled novel insights into the molecule mechanism of mRNA delivery by lipid nanoparticles (LNPs). In a recent study published in Nano Letters, a team lead by Jeehae Shin, PhD, in the Huan Bao laboratory, found that targeting recycling endosomes can vastly enhance the delivery of mRNA therapeutics.
Over the past two decades, mRNA-LNPs have demonstrated remarkable performance in therapeutics development, notably during the COVID-19 pandemic. Through LNP-mediated delivery, mRNAs encoding therapeutic proteins can be rapidly expressed in targeted cells and tissues to control a wide array of human diseases, including viral infections, cancer, immune disorders, and neurological conditions. Moreover, recent studies have successfully leveraged the robust expression of mRNA-LNPs with genome editing techniques to reprogram T cells for the development of powerful immunotherapies. However, despite significant progress, the low delivery efficiency of mRNA by LNPs remains a main barrier to unleashing the full potential of this powerful approach.
Through screening a panel of chemical modulators of membrane trafficking, Dr. Jeehae Shin identified two small molecules, NAV and ES5, significantly increase the delivery efficiencies of mRNA-LNPs. Further dissecting the underlying mechanism, the researchers found that NAV and ES5 target recycling endosomes to promote mRNA release. NAV blocks the activation of the essential regulator of endosomal trafficking, ARF-6, whereas ES5 suppresses the function of ANXA6 during early endosome biogenesis. These findings advance our understanding of mRNA-LNP biology and shed new light on the development of next-generation nucleic acid therapeutics.
This study was supported by National Institutes of Health DP2GM140920 and R21AG078699.
Filed Under: Research