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Drug Delivery

Poster Rapid Fire 1

Combinatorial Design of Siloxane-Incorporated Lipid Nanoparticles for Tissue-Specific mRNA Therapeutic Delivery

Thursday, October 12, 2023
1:05 PM – 1:10 PM PDT
Location: 346 (Center, Level 3)
Introduction:: Lipid nanoparticles (LNPs) have been shown to efficiently deliver mRNA therapeutics in vivo since the US Food and Drug Administration (FDA) authorized COVID-19 mRNA-LNP vaccines.1,2 However, when administered systemically, mRNA therapeutics preferentially accumulate in the liver, making extrahepatic delivery of mRNA therapeutics challenging.3 Currently, incorporation of additional charged components into LNPs formulations enabled mRNA delivery beyond liver, however, their safety and stability remain a problem. Owing to the high biocompatibility and stability of siloxane composites, herein we engineered a class of siloxane-derived lipid-like materials (siloxane lipidoids) into Siloxane LNPs (SiLNPs), and demonstrated systemic mRNA delivery to the liver, lung, and spleen by altering siloxane amine core and alkyl chain structures, enabling robust knockout of transthyretin (TTR) gene in the wide-type mice liver and efficient vascular regeneration in the lung damaged mice model.

Materials and Methods:: A library of 252 SiLNPs were screened in HepG2 cells. Top performing SiLNPs delivering firefly luciferase (Fluc) mRNA were intravenously administered into C57BL/6 mice, and luminescence was quantified to evaluate tissue-specific mRNA delivery. Liver- and lung-directed SiLNPs co-delivered Cas9 mRNA and functional single guide RNA to the liver of transthyretin (TTR) model and the lung of GFP transgene model, respectively. Lung-directed SiLNPs delivered Fibroblast Growth Factor 2 (FGF2) mRNA to the lung damaged model.


Results, Conclusions, and Discussions:: Followed by organized structure-activity relationship evaluation in vivo, we observed structure-guided tissue-targeted mRNA delivery profiles. Specifically, epoxide and ester tail-based SiLNPs delivered Fluc mRNA to the liver, amide bond tail-based SiLNPs delivered Fluc mRNA to the lung, and negative charged cyclic SiLNPs enable Fluc mRNA delivery to the spleen. Liver- and lung-directed SiLNPs co-delivering Cas9 mRNA and functional single guide RNA achieved potent gene editing in the liver of transthyretin (TTR) therapeutic model and in the lung of GFP transgene model, respectively. Lung-directed SiLNPs delivering FGF2 mRNA demonstrated efficient lung vascular regeneration in the lung damaged model.
By altering the structure of siloxane-derived amine heads and alkyl tails, organ-specific mRNA translation was realized, highlighting the importance of discovering novel LNP libraries for mRNA therapeutic delivery with tissue-tropism capability for protein replacement, gene editing, and genetic disease treatments.


Acknowledgements (Optional): :

References (Optional): : 1. Hou X et al. Nat. Rev. Mater., 2021, 6, 1078-1094. 2. Jackson S et al. Nature, 2021, 596, 109-113. 3. Cheng Q et al. Nat. Nanotechnol., 2020, 15, 313-320.