Martini 3 Building Blocks for Lipid Nanoparticle Design

Lipid nanoparticles (LNPs) represent a promising platform for advanced drug and gene delivery, yet optimizing these particles for specific cargos and cell targets poses a complex multifaceted challenge. Furthermore, there is a pressing need for a more comprehensive understanding of the underlying technology. Experimental studies are costly and often provide low-resolution information. Molecular dynamics (MD) simulations allow us to study these particles at a higher resolution, enhancing our understanding. However, studying these systems at atomic resolutions is both challenging and computationally expensive as well as time-consuming. Coarse-grained (CG) models, such as Martini 3, are positioned as promising tools for studying LNPs. To enable CG-MD studies of LNPs, accurate and validated models of their components are needed. Here, we present a substantial extension of the Martini 3 lipid library, introducing over one hundred ionizable lipid models, natural sterols, and PEGylated lipids, covering the key components of LNP formulations. This expanded library brings an essential toolset to simulate LNPs at Martini coarse-grained resolution. We furthermore introduce initial protocols for screening fusion efficacy across lipid formulations and for constructing full LNPs and show how these tools can provide new insights into the LNP structure, dynamics, and efficiency. Altogether, this work introduces a practical and scalable approach for advancing the mechanistic understanding of LNPs and guiding their future development.

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Publication Details

Journal
Journal of Chemical Theory and Computation
Published
2025-12-17
DOI
https://doi.org/10.1021/acs.jctc.5c01207
Citations
5
Primary Topic
RNA Interference and Gene Delivery
Type
article
Field-Weighted Citation Impact
4.03
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Martini 3 Building Blocks for Lipid Nanoparticle Design

Mariana Valério, Raúl Mera‐Adasme, Paulo C. T. Souza, Rocío Araya‐Osorio et al.
5 citations
Journal of Chemical Theory and Computation
RNA Interference and Gene Delivery
4.03
article

Martini 3 Building Blocks for Lipid Nanoparticle Design

Mariana Valério, Raúl Mera‐Adasme, Paulo C. T. Souza, Rocío Araya‐Osorio, Bart M. H. Bruininks, Fabian Grünewald, Martin Šrejber, Michal Otyepka, Roberto Pestana-Nobles, Sangwook Wu, Luís Borges-Araújo, ‪Siewert J. Marrink, Markéta Paloncýová, Luca Monticelli, Lisbeth R. Kjølbye
article en
5 citations

Abstract

Lipid nanoparticles (LNPs) represent a promising platform for advanced drug and gene delivery, yet optimizing these particles for specific cargos and cell targets poses a complex multifaceted challenge. Furthermore, there is a pressing need for a more comprehensive understanding of the underlying technology. Experimental studies are costly and often provide low-resolution information. Molecular dynamics (MD) simulations allow us to study these particles at a higher resolution, enhancing our understanding. However, studying these systems at atomic resolutions is both challenging and computationally expensive as well as time-consuming. Coarse-grained (CG) models, such as Martini 3, are positioned as promising tools for studying LNPs. To enable CG-MD studies of LNPs, accurate and validated models of their components are needed. Here, we present a substantial extension of the Martini 3 lipid library, introducing over one hundred ionizable lipid models, natural sterols, and PEGylated lipids, covering the key components of LNP formulations. This expanded library brings an essential toolset to simulate LNPs at Martini coarse-grained resolution. We furthermore introduce initial protocols for screening fusion efficacy across lipid formulations and for constructing full LNPs and show how these tools can provide new insights into the LNP structure, dynamics, and efficiency. Altogether, this work introduces a practical and scalable approach for advancing the mechanistic understanding of LNPs and guiding their future development.

Journal of Chemical Theory and ComputationVol. 22(2)
Université Claude Bernard Lyon 1 (FR), École Normale Supérieure de Lyon (FR), Centre National de la Recherche Scientifique (FR), Biotechnology Institute (US), University of Helsinki (FI), VSB - Technical University of Ostrava (CZ), Inserm (FR), University of Groningen (NL), University of Tarapacá (CL), Structural and Molecular Basis of Infectious Systems (FR), Korea Pharma (South Korea) (KR), Regional Centre of Advanced Technologies and Materials (CZ), Universidad Simón Bolívar (CO), Palacký University Olomouc (CZ), Heidelberg Institute for Theoretical Studies (DE), Pukyong National University (KR)
Openalex Percentile: Top 6%
RNA Interference and Gene Delivery
4.03
DOIOpen Access PDFOpenAlex
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