Understanding Intracellular Biology to Improve mRNA Delivery by Lipid Nanoparticles.

Autor: Hunter MR; Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Cambridge, CB21 6GH, UK., Cui L; Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Cambridge, CB21 6GH, UK., Porebski BT; Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Cambridge, CB2 0QH, UK., Pereira S; Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Cambridge, CB21 6GH, UK., Sonzini S; Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Cambridge, CB21 6GH, UK., Odunze U; Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Cambridge, CB21 6GH, UK., Iyer P; Molecular AI, Discovery Sciences, R&D, Astrazeneca, Gothenburg, 431 50, Sweden., Engkvist O; Molecular AI, Discovery Sciences, R&D, Astrazeneca, Gothenburg, 431 50, Sweden., Lloyd RL; Functional Genomics, Discovery Sciences, R&D, AstraZeneca, Cambridge, CB4 0WG, UK., Peel S; Functional Genomics, Discovery Sciences, R&D, AstraZeneca, Cambridge, CB4 0WG, UK., Sabirsh A; Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, 431 50, Sweden., Ross-Thriepland D; Functional Genomics, Discovery Sciences, R&D, AstraZeneca, Cambridge, CB4 0WG, UK., Jones AT; Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, CF10 3NB, UK., Desai AS; Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Cambridge, CB21 6GH, UK.
Jazyk: angličtina
Zdroj: Small methods [Small Methods] 2023 Sep; Vol. 7 (9), pp. e2201695. Date of Electronic Publication: 2023 Jun 14.
DOI: 10.1002/smtd.202201695
Abstrakt: Poor understanding of intracellular delivery and targeting hinders development of nucleic acid-based therapeutics transported by nanoparticles. Utilizing a siRNA-targeting and small molecule profiling approach with advanced imaging and machine learning biological insights is generated into the mechanism of lipid nanoparticle (MC3-LNP) delivery of mRNA. This workflow is termed Advanced Cellular and Endocytic profiling for Intracellular Delivery (ACE-ID). A cell-based imaging assay and perturbation of 178 targets relevant to intracellular trafficking is used to identify corresponding effects on functional mRNA delivery. Targets improving delivery are analyzed by extracting data-rich phenotypic fingerprints from images using advanced image analysis algorithms. Machine learning is used to determine key features correlating with enhanced delivery, identifying fluid-phase endocytosis as a productive cellular entry route. With this new knowledge, MC3-LNP is re-engineered to target macropinocytosis, and this significantly improves mRNA delivery in vitro and in vivo. The ACE-ID approach can be broadly applicable for optimizing nanomedicine-based intracellular delivery systems and has the potential to accelerate the development of delivery systems for nucleic acid-based therapeutics.
(© 2023 The Authors. Small Methods published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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