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In Silico Screening Accelerates Nanocarrier Design for Efficient mRNA Delivery.

ABSTRACT: Lipidic nanocarriers are a broad class of lipid-based vectors with proven potential for packaging and delivering emerging nucleic acid therapeutics. An important early step in the clinical development cycle is large-scale screening of diverse formulation libraries to assess particle quality and payload delivery efficiency. Due to the size of the screening space, this process can be both costly and time-consuming. To address this, computational models capable of predicting clinically relevant physio-chemical properties of dendrimer-lipid nanocarriers, along with their mRNA payload delivery efficiency in human cells are developed. The models are then deployed on a large theoretical nanocarrier pool consisting of over 4.5 million formulations. Top predictions are synthesised for validation using cell-based assays, leading to the discovery of a high quality, high performing, candidate. The methods reported here enable rapid, high-throughput, in silico pre-screening for high-quality candidates, and have great potential to reduce the cost and time required to bring mRNA therapies to the clinic.

SUBMITTER: Henser-Brownhill T

PROVIDER: S-EPMC11321627 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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In Silico Screening Accelerates Nanocarrier Design for Efficient mRNA Delivery.

Henser-Brownhill Tristan T Martin Liam L Samangouei Parisa P Ladak Aaqib A Apostolidou Marina M Nagel Benita B Kwok Albert A

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20240605 30

Lipidic nanocarriers are a broad class of lipid-based vectors with proven potential for packaging and delivering emerging nucleic acid therapeutics. An important early step in the clinical development cycle is large-scale screening of diverse formulation libraries to assess particle quality and payload delivery efficiency. Due to the size of the screening space, this process can be both costly and time-consuming. To address this, computational models capable of predicting clinically relevant phy ...[more]

PMID: 38837626

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Project description:Lipid nanoparticles (LNPs) have emerged as an effective and promising technology for messenger RNA (mRNA) delivery, offering a potential solution to physiological barriers and providing an alternative approach to gene therapy without the drawbacks associated with viral delivery. However, efficiently delivering mRNA remains a significant challenge in nucleic acid-based therapies due to the limitations of current LNP platforms in achieving optimal endosomal escape and mRNA release, which largely relies on finding a suitable ionizable lipid. Additionally, the synthesis of these ionizable lipids involves multiple chemical reactions, often making the process time-consuming and difficult to translate. In this study, we employed a facile, catalyst-free, and versatile one-pot multicomponent reaction (MCR) to develop a library of ionizable lipids featuring a pharmacologically significant tetrahydropyrimidine (THP) backbone, tailored for enhanced mRNA delivery. A library of 26 THP ionizable lipids was systematically synthesized in just 3 h and formulated with luciferase mRNA for initial in vitro screening. The THP LNPs exhibited tunable particle sizes, favorable ζ-potentials, and high encapsulation efficiencies. Among them, THP1 demonstrated the highest transfection efficiency both in vitro and in vivo after intramuscular administration, comparable to DLin-MC3-DMA (MC3), a conventional benchmark. Further optimization of THP1 with phospholipids significantly enhanced intramuscular mRNA delivery and showed sustained protein expression in vivo for up to 5 days. More importantly, it demonstrated successful intravenous delivery in a dose-dependent manner with minimal toxicity, as indicated by hematological, histopathological, and proinflammatory cytokine assessments. Furthermore, THP1 LNPs also demonstrated the ability to edit genes in specific liver tissues in a tdTomato transgenic mouse model, highlighting their precision and utility in targeted therapeutic applications. These findings position THP1 LNPs as promising candidates for advancing mRNA-based therapies, with significant implications for clinical translation in vaccine delivery and CRISPR/Cas9-mediated gene editing in the liver.

Dataset Information

In Silico Screening Accelerates Nanocarrier Design for Efficient mRNA Delivery.

Publications

In Silico Screening Accelerates Nanocarrier Design for Efficient mRNA Delivery.

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