RNA therapy is a disruptive technology comprising a rapidly expanding category of drugs. Further translation of RNA therapies to the clinic will improve the treatment of many diseases and help enable personalized medicine. However, in vivo delivery of RNA remains challenging due to the lack of appropriate delivery tools. Current state-of-the-art carriers such as ionizable lipid nanoparticles still face significant challenges, including frequent localization to clearance-associated organs and limited (1–2%) endosomal escape. Thus, delivery vehicles must be improved to further unlock the full potential of RNA therapeutics. An emerging strategy is to modify existing or new lipid nanocarriers by incorporating bioinspired design principles. This method generally aims to improve tissue targeting, cellular uptake, and endosomal escape, addressing some of the critical issues facing the field. In this review, we introduce the different strategies for creating bioinspired lipid-based RNA carriers and discuss the potential implications of each strategy based on reported findings. These strategies include incorporating naturally derived lipids into existing nanocarriers and mimicking bioderived molecules, viruses, and exosomes. We evaluate each strategy based on the critical factors required for delivery vehicles to succeed. Finally, we point to areas of research that should be furthered to enable the more successful rational design of lipid nanocarriers for RNA delivery.
Ionizable lipid nanoparticles (LNPs) have seen widespread use in mRNA delivery for clinical applications, notably in SARS-CoV-2 mRNA vaccines. Despite their successful use, expansion of mRNA therapies beyond COVID-19 is impeded by the absence of LNPs tailored to different target cell types. The traditional process of LNP development remains labor-intensive and cost-inefficient, relying heavily on trial and error. In this study, we present the AI-Guided Ionizable Lipid Engineering (AGILE) platform, a synergistic combination of deep learning and combinatorial chemistry. AGILE streamlines the iterative development of ionizable lipids, crucial components for LNP-mediated mRNA delivery. This approach brings forth three significant features: efficient design and synthesis of combinatorial lipid libraries, comprehensive in silico lipid screening employing deep neural networks, and adaptability to diverse cell lines. Using AGILE, we were able to rapidly design, synthesize, and evaluate new ionizable lipids for mRNA delivery in muscle and immune cells, selecting from a library of over 10,000 candidates. Importantly, AGILE has revealed cell-specific preferences for ionizable lipids, indicating the need for different tail lengths and head groups for optimal delivery to varying cell types. These results underscore the potential of AGILE in expediting the development of customized LNPs. This could significantly contribute to addressing the complex needs of mRNA delivery in clinical practice, thereby broadening the scope and efficacy of mRNA therapies.
In 2018, LNPs enabled the first FDA approval of a siRNA drug (Onpattro); two years later, two SARS-CoV-2 vaccines (Comirnaty, Spikevax) based on LNPs containing mRNA also arrived at the...
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