The following study was conducted by Scientists from Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Ming Wai Lau Centre for Reparative Medicine, Karolinska Institutet, Hong Kong, China; Department of Anesthesiology, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA, USA; Division of Regenerative Medicine and Cellular Therapy, University of Nottingham, Nottingham, UK; Department of Molecular Biology, Massachusetts General Hospital, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Cambridge, MA, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA; Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA. Study is published in Nature Communications Journal as detailed below
Nature Communications; Volume 11, Article Number: 2424 (2020)
Synergistic Lipid Compositions for Albumin Receptor Mediated Delivery of mRNA to the Liver
Abstract
Lipid-like nanoparticles (LNPs) have potential as non-viral delivery systems for mRNA therapies. However, repeated administrations of LNPs may lead to accumulation of delivery materials and associated toxicity. To address this challenge, we have developed biodegradable lipids which improve LNPs clearance and reduce toxicity. We modify the backbone structure of Dlin-MC3-DMA by introducing alkyne and ester groups into the lipid tails. We evaluate the performance of these lipids when co-formulated with other amine containing lipid-like materials. We demonstrate that these formulations synergistically facilitate robust mRNA delivery with improved tolerability after single and repeated administrations. We further identify albumin-associated macropinocytosis and endocytosis as an ApoE-independent LNP cellular uptake pathway in the liver. Separately, the inclusion of alkyne lipids significantly increases membrane fusion to enhance mRNA release, leading to synergistic improvement of mRNA delivery. We believe that the rational design of LNPs with multiple amine-lipids increases the material space for mRNA delivery.
Source:
Nature Communications
URL: https://www.nature.com/articles/s41467-020-16248-y
Citation:
Miao, L., J. Lin, et al. (2020). “Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver.” Nature Communications 11(1): 2424.
