Modeling lipid nanoparticle transport in extracellular matrix: Effects of particle size and rigidity

Abstract

Lipid nanoparticles (LNPs) traverse through multiple biological barriers, such as crosslinked mesh structures in the extracellular matrix, before reaching their target sites. The physicochemical properties of LNPs determine their ability to penetrate complex biological environments such as the brain extracellular matrix. Their deformation in polymeric matrices affects transport, making it crucial to understand these factors for effective therapeutic delivery. Here, we develop a highly Coarse-Grained (CG) model of the LNP and its surrounding polymeric matrix, simulated as a uniform grid of cross-linked hyaluronic acid (HA) chains. The model for highly coarse-grained LNP was developed from a one-particle-thick membrane model that maintains mechanical features of lipid membranes, such as fluidity, topological changes, and hydrodynamic effects. Here, we investigate the collective influence of lipid nanoparticle size and its bending rigidity on the diffusive transport through the biological matrix. Our work highlights the role of particle to matrix size ratio in understanding deformation-assisted diffusive transport of LNPs in the matrix environment. Our study provides a tool to disentangle the effects of particle size and their bending rigidity on the transport through complex environments. Furthermore, this study systematically complements the rational design of lipid nanoparticle-based drug delivery platforms. SIGNIFICANCELipid nanoparticles (LNPs) are emerging as a powerful platform for delivering nucleic acid-based therapeutics, especially to hard-to-reach tissues like the brain. Their ability to protect and transport charged molecules, such as mRNA or siRNA, offers promising strategies for treating neurological disorders and advancing precision medicine for aging demographics around the world. In the brain parenchyma, LNPs must navigate the dense and heterogeneous extracellular matrix (ECM), composed primarily of crosslinked hyaluronic acid and proteoglycans. Understanding how particle size, deformability, and shape parameter affect the transport through this complex environment is critical for optimizing drug delivery platforms.