Anomalous Diffusion of Nanoparticles in Semidilute Hyaluronic Acid Solutions

Efficient drug delivery using nanoparticles (NPs) depends on their ability to diffuse through biological tissues. The extracellular matrix (ECM) poses a key transport barrier, directly influencing biodistribution, cellular uptake, and therapeutic efficacy. A primary transport regulator is hyaluronic acid (HA), a major ECM polysaccharide forming a viscoelastic network. Changes in HA concentration alter ECM effective viscosity, while steric obstruction and hydrodynamic drag hinder nanoscale NP mobility. Because HA molecular weights and concentrations vary widely across ages, tissues, and pathologies, we investigated NP diffusion in diverse HA polymer mixtures using dynamic light scattering (DLS). These experiments were complemented by coarse-grained molecular dynamics (CG-MD) simulations. We observed anomalous NP diffusion strongly dictated by the particle-to-network size ratio, particularly in high-molecular-weight mixtures. This transport is governed by the local effective viscosity. Our work establishes a simulation-coupled predictive framework of NP diffusion within specific ECM environments.