When and How Ultrasound Enhances Nanoparticle Diffusion in Hydrogels: A Stick-and-Release Mechanism

TL;DR

This study uses simulations to reveal that ultrasound enhances nanoparticle diffusion in hydrogels through a stick-and-release mechanism, especially when particle-matrix interactions are strong and ultrasound pulses are sufficiently long.

Contribution

It provides a molecular-level explanation for ultrasound-enhanced nanoparticle diffusion in hydrogels, clarifying previous contradictory experimental results.

Findings

Ultrasound reduces contact time between nanoparticles and hydrogel matrix.

Enhanced diffusion occurs when nanoparticle-hydrogel interactions are strong.

Long ultrasound pulses disrupt nanoparticle-matrix interactions, enabling diffusion.

Abstract

Nanoparticles (NPs) are widely used as drug carriers in cancer therapy due to their ability to accumulate in tumor tissue via the enhanced permeability and retention effect. However, their transport within tumors is often hindered by the dense extracellular matrix, where diffusion dominates. Several studies suggest that ultrasound (US) irradiation can enhance NP diffusion in ECM-mimicking hydrogels, yet the underlying molecular mechanisms remain unclear, and experimental findings are often contradictory. Here, we use coarse-grained Langevin Dynamics simulations to investigate the conditions under which US can enhance NP diffusion in hydrogels. After validating our simulation framework against an exact analytical solution for NP motion under US in dilute buffer, we systematically explore NP diffusion in hydrogels with varying degrees of NP-network attraction. Our results reveal that acoustic enhancement arises from reduced contact time between NPs and the hydrogel matrix. This effect becomes significant only when NP-hydrogel interactions are sufficiently strong and US pulses are long enough to disrupt these interactions, following a "stick-and-release" mechanism. These findings reconcile previously conflicting experimental observations and explain why acoustic enhancement is observed in some studies but not others. Overall, our study provides a molecular-level explanation for US-enhanced NP diffusion in hydrogels and establishes design principles for optimizing therapeutic US protocols in drug delivery applications.