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Understanding Intracellular Biology to Improve mRNA Delivery by Lipid Nanoparticles

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 mecha...

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Detalles Bibliográficos
Autores principales: Hunter, Morag Rose, Cui, Lili, Porebski, Benjamin Thomas, Pereira, Sara, Sonzini, Silvia, Odunze, Uchechukwu, Iyer, Preeti, Engkvist, Ola, Lloyd, Rebecca Louise, Peel, Samantha, Sabirsh, Alan, Ross-Thriepland, Douglas, Jones, Arwyn Tomos, Desai, Arpan Shailesh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7615154/
https://www.ncbi.nlm.nih.gov/pubmed/37317010
http://dx.doi.org/10.1002/smtd.202201695
Descripción
Sumario: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.