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

Lipid nanoparticles (LNPs) traverse through multiple biological barriers, such as cross-linked 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's 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 CG LNPs 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 LNP size and its bending rigidity on the diffusive transport through the biological matrix. Our work highlights the role of the particle/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 LNP-based drug delivery platforms.