Sheng Zhao, Kewa Gao, Hesong Han, Michael Stenzel, Boyan Yin, Hengyue Song, Atip Lawanprasert, Josefine Eilsø Nielsen, Rohit Sharma, Opeyemi H. Arogundade, Sopida Pimcharoen, Yu-Ju Chen, Abhik Paul, Jan Tuma, Michael G. Collins, Yofiel Wyle, Matileen Grace Cranick, Benjamin W. Burgstone, Barbara S. Perez, Annelise E. Barron, Andrew M. Smith, Hye Young Lee, Aijun Wang, Niren Murthy
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引用次数: 0
Abstract
Lipid nanoparticle (LNP)–mRNA complexes are transforming medicine. However, the medical applications of LNPs are limited by their low endosomal disruption rates, high toxicity and long tissue persistence times. LNPs that rapidly hydrolyse in endosomes (RD-LNPs) could solve the problems limiting LNP-based therapeutics and dramatically expand their applications but have been challenging to synthesize. Here we present an acid-degradable linker termed ‘azido-acetal’ that hydrolyses in endosomes within minutes and enables the production of RD-LNPs. Acid-degradable lipids composed of polyethylene glycol lipids, anionic lipids and cationic lipids were synthesized with the azido-acetal linker and used to generate RD-LNPs, which significantly improved the performance of LNP–mRNA complexes in vitro and in vivo. Collectively, RD-LNPs delivered mRNA more efficiently to the liver, lung, spleen and brains of mice and to haematopoietic stem and progenitor cells in vitro than conventional LNPs. These experiments demonstrate that engineering LNP hydrolysis rates in vivo has great potential for expanding the medical applications of LNPs. A new acid-degradable linker termed ‘azido-acetal’ has been developed that rapidly hydrolyses at pH 6.0 but is stable at pH 7.4. Lipid nanoparticles made with this linker delivered mRNA in vivo and in vitro better than traditional lipid nanoparticles.
期刊介绍:
Nature Nanotechnology is a prestigious journal that publishes high-quality papers in various areas of nanoscience and nanotechnology. The journal focuses on the design, characterization, and production of structures, devices, and systems that manipulate and control materials at atomic, molecular, and macromolecular scales. It encompasses both bottom-up and top-down approaches, as well as their combinations.
Furthermore, Nature Nanotechnology fosters the exchange of ideas among researchers from diverse disciplines such as chemistry, physics, material science, biomedical research, engineering, and more. It promotes collaboration at the forefront of this multidisciplinary field. The journal covers a wide range of topics, from fundamental research in physics, chemistry, and biology, including computational work and simulations, to the development of innovative devices and technologies for various industrial sectors such as information technology, medicine, manufacturing, high-performance materials, energy, and environmental technologies. It includes coverage of organic, inorganic, and hybrid materials.