Membrane-Specific Binding of 4 nm Lipid Nanoparticles Mediated by an Entropy-Driven Interaction Mechanism

Abstract

Lipid nanoparticles (LNPs) are a leading biomimetic drug delivery platform due to their distinctive advantages and highly tunable formulations. A mechanistic understanding of the interaction between LNPs and cell membranes is essential for developing the cell-targeted carriers for precision medicine. Here the interactions between sub 10 nm cationic LNPs (cLNPs; e.g., 4 nm in size) and varying model cell membranes are systematically investigated using molecular dynamics simulations. We find that the membrane-binding behavior of cLNPs is governed by a two-step mechanism that is initiated by direct contact followed by a more crucial lipid exchange (dissociation of cLNP’s coating lipids and subsequent flip and intercalation into the membrane). Importantly, our simulations demonstrate that the membrane binding of cLNPs is an entropy-driven process, which thus enables cLNPs to differentiate between membranes having different lipid compositions (e.g., the outer and inner membranes of bacteria vs the red blood cell membranes). Accordingly, the possible strategies to drive the membrane-targeting behaviors of cLNPs, which mainly depend on the entropy change in the complicated entropy–enthalpy competition of the cLNP–membrane interaction process, are investigated. Our work unveils the molecular mechanism underlying the membrane selectivity of cLNPs and provides useful hints to develop cLNPs as membrane-targeting agents for precision medicine.

Converting Nanotoxicity Data to Information Using Artificial Intelligence and Simulation

“…621 Recently, the preferential binding of NPs on membranes of various compositions was found to be an entropydriven process. 622 The gel-phase membrane patch is stiffer and more resistant to bending, as analyzed by previous simulations. 623 Thus, NPs are more challenging to be wrapped by the gel-phase membrane, due to the higher energy cost of membrane bending.…”

High‐Precision Synthesis of RNA‐Loaded Lipid Nanoparticles for Biomedical Applications

“…[ 79 ] Moreover, these unsaturated alkyl chains can also act as immunomodulators by contributing to membrane destabilization and fusogenicity. [ 80–82 ] Ou et al. reported that a higher extent of unsaturated cationic lipids in LNP facilitates membrane contact and increases the membrane‐binding probability than analogous LNP with saturated cationic lipids.…”

“…The authors also demonstrated that increasing the degree of unsaturation in lipid tails yields LNP with a loosely packed structure and promotes lipid exchange at the membrane, which was verified by calculation of the lipid exchange rate and increase of entropy. [ 82 ] In fact, a low degree of saturation in lipids leads to a low transition temperature and thus facile formation of inverted micelles, and even inverted hexagonal lipid phase (H II ). For instance, synthetic spermine‐derived lipopolyamines with a lower degree of saturation have shown increased gene silencing efficiency.…”

“…[79] Moreover, these unsaturated alkyl chains can also act as immunomodulators by contributing to membrane destabilization and fusogenicity. [80][81][82] Ou et al reported that a higher extent of unsaturated cationic lipids in LNP facilitates membrane contact and increases the membrane-binding probability than analogous LNP with saturated cationic lipids. The authors also demonstrated that increasing the degree of unsaturation in lipid tails yields LNP with a loosely packed structure and promotes lipid exchange at the membrane, which was verified by calculation of the lipid exchange rate and increase of entropy.…”

Thermal-controlled cellular uptake of “hot” nanoparticles

“…21,22 With specific coating lipids, these NPs demonstrate excellent targeting abilities for membranes and even tissues, showing great potential in precision medicine. [23][24][25][26][27][28] However, given the intricate nature of biological processes and the growing need to expand the potential biomedical applications of NPs, further efforts are required to develop novel regulatory strategies for NP cellular uptake, such as exploring new NP species or properties and investigating alternative modes of membrane-NP interactions. [29][30][31][32][33][34][35] Photothermal therapy (PTT) has garnered significant attention in recent years as a promising noninvasive technique for tumor treatment.…”