Regime of Geometrical Mismatch in the Phase Separation-Regulated Endocytosis of Nanoparticles

The biological responses related to microdomains formed by phase separation in cell membranes bear long-standing controversies, and, in particular, how this lateral heterogeneity impacts the cellular uptake of nanoparticles remains poorly understood. By combining theoretical models, computer simulations, and experimental discussions, we report on an unconventionally constrained regime of nanoparticle endocytosis on the membrane microdomain, emerging within the intermediate scale of the domains. This regime leads to the nonmonotonic dependence of nanoparticle endocytosis on domain size, in stark contrast to its counterparts in the homogeneous membrane and endocytosis without nanoparticles. Theoretical analysis evaluates the regime boundary and reveals that the regime arises from the geometrical mismatch between nanoparticles and microdomains governed by various energetic contributions, which capture and explain some experimental observations. The findings suggest an appealing way and useful guidelines to control cellular uptake and might be of immediate interest to the desired biomedical applications.