Kaitlin Mrksich, Marshall S. Padilla, Ryann A. Joseph, Emily L. Han, Dongyoon Kim, Rohan Palanki, Junchao Xu, Michael J. Mitchell
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引用次数: 0
Abstract
RNA-based therapeutics have gained traction for the prevention and treatment of a variety of diseases. However, their fragility and immunogenicity necessitate a drug carrier. Lipid nanoparticles (LNPs) have emerged as the predominant delivery vehicle for RNA therapeutics. An important component of LNPs is the ionizable lipid (IL), which is protonated in the acidic environment of the endosome, prompting cargo release into the cytosol. Currently, there is growing evidence that the structure of IL lipid tails significantly impacts the efficacy of LNP-mediated mRNA translation. Here, we optimized IL tail length for LNP-mediated delivery of three different mRNA cargos. Using C12-200, a gold standard IL, as a model, we designed a library of ILs with varying tail lengths and evaluated their potency in vivo. We demonstrated that small changes in lipophilicity can drastically increase or decrease mRNA translation. We identified that LNPs formulated with firefly luciferase mRNA (1929 base pairs) and C10-200, an IL with shorter tail lengths than C12-200, enhance liver transfection by over 10-fold. Furthermore, different IL tail lengths were found to be ideal for transfection of LNPs encapsulating mRNA cargos of varying sizes. LNPs formulated with erythropoietin (EPO), responsible for stimulating red blood cell production, mRNA (858 base pairs), and the C13-200 IL led to EPO translation at levels similar to the C12-200 LNP. The LNPs formulated with Cas9 mRNA (4521 base pairs) and the C9-200 IL induced over three times the quantity of indels compared with the C12-200 LNP. Our findings suggest that shorter IL tails may lead to higher transfection of LNPs encapsulating larger mRNAs, and that longer IL tails may be more efficacious for delivering smaller mRNA cargos. We envision that the results of this project can be utilized as future design criteria for the next generation of LNP delivery systems for RNA therapeutics.
期刊介绍:
The Journal of Biomedical Materials Research Part A is an international, interdisciplinary, English-language publication of original contributions concerning studies of the preparation, performance, and evaluation of biomaterials; the chemical, physical, toxicological, and mechanical behavior of materials in physiological environments; and the response of blood and tissues to biomaterials. The Journal publishes peer-reviewed articles on all relevant biomaterial topics including the science and technology of alloys,polymers, ceramics, and reprocessed animal and human tissues in surgery,dentistry, artificial organs, and other medical devices. The Journal also publishes articles in interdisciplinary areas such as tissue engineering and controlled release technology where biomaterials play a significant role in the performance of the medical device.
The Journal of Biomedical Materials Research is the official journal of the Society for Biomaterials (USA), the Japanese Society for Biomaterials, the Australasian Society for Biomaterials, and the Korean Society for Biomaterials.
Articles are welcomed from all scientists. Membership in the Society for Biomaterials is not a prerequisite for submission.