Enzyme-Regulated Non-Thermal Fluctuations Enhance Ligand Diffusion and Receptor-Mediated Endocytosis

Active enzymes during catalyzing chemical reactions, have been found to generate significant mechanical fluctuations, which can influence the dynamics of their surroundings. These phenomena open new avenues for controlling mass transport in complex and dynamically inhomogeneous environments through localized chemical reactions. To explore this potential, we studied the uptake of transferrin molecules in retinal pigment epithelium (RPE) cells via clathrin-mediated endocytosis. In the presence of enzyme catalysis in the extracellular matrix, we observed a significant enhancement in the transport of fluorophore-tagged transferrin inside the cells. Fluorescence correlation spectroscopy measurements showed substantial increase in transferrin diffusion in the presence of active fluctuations. This study sheds light on the possibility that enzyme-substrate reactions within the extracellular matrix may induce long-range mechanical influences, facilitating targeted material delivery within intracellular milieu more efficiently than passive diffusion. These insights are expected to contribute to the development of better therapeutic strategies by overcoming limitations imposed by slow molecular diffusion under complex environments.