Amphiphilic Janus nanoparticles, which are hydrophilic on one-half of the particle surface and hydrophobic on the other half, are ideal carrier candidates for drug delivery due to their unique physicochemical properties. In this study, we investigate the interactions between amphiphilic Janus nanoparticles coated with hydrophilic and hydrophobic ligands on each half of the surface of the nanoparticle and lipid bilayers with either symmetric or asymmetric leaflet structure and in different phases using atomistic molecular dynamics simulations. The results show that the Janus nanoparticle can easily insert into the liquid-disordered lipid bilayer and asymmetric lipid bilayers with the hydrophobic ligands inserted into the liquid-ordered leaflet. However, the nanoparticle barely inserts into the symmetric liquid-ordered lipid bilayer and tends to be adsorbed onto the surface of the liquid-ordered bilayers with the hydrophilic ligands contacting the surface of the bilayer. The insertion of the nanoparticle is mainly dominated by the hydrophobicity of the ligands, the lipid ordering, and the curvature of the bilayer. Rotation of the nanoparticle only occurs during the initial adsorption process of the nanoparticle onto the surface of the lipid bilayers. This work provides new insight into understanding the interactions of amphiphilic Janus nanoparticles with model biological membranes at the atomistic scale and the application of Janus nanoparticles for drug delivery.

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.

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...

The in vivo dynamics of nanoparticles requires a mechanistic understanding of multiple factors. Here, for the first time, the surprising breakdown of functionalized gold nanostars (F‐AuNSs) conjugated with antibodies and 64Cu radiolabels in vivo and in artificial lysosomal fluid ex vivo, is shown. The short‐term biodistribution of F‐AuNSs is driven by the route of systemic delivery (intravenous vs intraperitoneal) and long‐term fate is controlled by the tissue type in vivo. In vitro studies including endocytosis pathways, intracellular trafficking, and opsonization, are combined with in vivo studies integrating a milieu of spectroscopy and microcopy techniques that show F‐AuNSs dynamics is driven by their physicochemical properties and route of delivery. F‐AuNSs break down into sub‐20 nm broken nanoparticles as early as 7 days postinjection. Martini coarse‐grained simulations are performed to support the in vivo findings. Simulations suggest that shape, size, and charge of the broken nanoparticles, and composition of the lipid membrane depicting various tissues govern the interaction of the nanoparticles with the membrane, and the rate of translocation across the membrane to ultimately enable tissue clearance. The fundamental study addresses critical gaps in the knowledge regarding the fate of nanoparticles in vivo that remain a bottleneck in their clinical translation.