Thermal-controlled cellular uptake of “hot” nanoparticles

Abstract

Nanoparticles (NPs) have shown immense potential in the field of biomedical applications, particularly in NP-based photothermal therapy, which offers a remote-controlled approach to achieve precise temperature control for site-specific heating and sub-cellular tumor treatment. However, the molecular mechanisms underlying related cellular activities, such as the cellular uptake behavior of irradiated NPs in photothermal effects, remain elusive. In this study, we conducted a thorough investigation of the interaction between an irradiated NP with elevated temperature (ranging from 270 to 360 K) and a model bilayer membrane composed of DPPC or DOPC using nonequilibrium coarse-grained molecular dynamics simulations with the implicit-solvent Dry Martini force field. We observe that the interaction between a “hot” NP and a membrane is thermally regulated. In addition, the wrapping of membranes around NPs exhibits a strong dependence on the temperature of the irradiated NP, demonstrating a step-like change in behavior. This membrane wrapping effect is attributed to the heat conduction between NPs and membrane lipids, which occurs almost simultaneously with the membrane deformation and wrapping of NPs during the NP–membrane interaction process. Especially, during the process of heat conduction, a gel-to-fluid phase transition of the membrane may occur, which plays a crucial role in determining the deformation behavior of the membrane. Moreover, it is found that the membrane lipids in the two leaflets exhibit obvious and asymmetric molecular-level responses to heat flux, characterized by significant changes in packing states (e.g., the order parameter of lipid tails and area per lipid) and possible interdigitation between lipids. Furthermore, the thermal-controlled wrapping effect is tightly linked to the properties of NPs (e.g., size, NP-lipid affinity) and lipid species. Our findings are valuable for comprehending the thermal-regulated cellular internalization of NPs and offer insights into devising strategies to precisely modulate NP endocytosis by exploiting the interplay between heating and NP properties.