Multiphysics modeling and simulation of local transport and absorption kinetics of intramuscularly injected lipid nanoparticles.

Abstract

Recent clinical applications of mRNA vaccines highlight the critical role of drug delivery, especially when using lipid nanoparticles (LNPs) as the carrier for genetic payloads. However, kinetic and transport mechanisms for locally injected LNPs, such as lymphatic or cellular uptake and drug release, remain poorly understood. Herein, we developed a bottom-up multiphysics computational model to simulate the injection and absorption processes of LNPs in muscular tissues. Our purpose was to seek underlying connections between formulation attributes and local exposure kinetics of LNPs and the delivered drug. We were also interested in modeling the absorption kinetics from the local injection site to the systemic circulation. In our model, the tissue was treated as the homogeneous, poroelastic medium in which vascular and lymphatic vessel densities are considered. Tissue deformation and interstitial fluid flow (modeled using Darcy's Law) were also implemented. Transport of LNPs was described based on diffusion and advection; local disintegration and cellular uptake were also integrated. Sensitivity analyses of LNP and drug properties and tissue attributes were conducted using the simulation model. It was found that intrinsic tissue porosity and lymphatic vessel density affect the local transport kinetics; diffusivity, lymphatic permeability, and intracellular update kinetics also play critical roles. Simulated results were commensurate with experimental observations. This study could shed light on the development of LNP formulations and enable further development of whole-body pharmacokinetic models.