Nanovesicles are closed, bubblelike surfaces with a diameter between 20 and 200 nm, formed by lipid bilayers and biomembranes. Electron microscopy (EM) studies have shown that these vesicles can attain both spherical and nonspherical shapes. One disadvantage of EM methods is that they provide only a single snapshot of each vesicle. Here, we use molecular dynamics simulations to monitor the morphological transformations of individual nanovesicles. We start with the assembly of spherical vesicles that enclose a certain volume of water and contain a certain total number of lipids. When we reduce their volume, the spherical vesicles are observed to transform into a multitude of nonspherical shapes such as oblates and stomatocytes as well as prolates and dumbbells. This surprising polymorphism can be controlled by redistributing a small fraction of lipids between the inner and outer leaflets of the bilayer membranes. As a consequence, the inner and the outer leaflets experience different mechanical tensions. Small changes in the vesicle volume reduce the overall bilayer tension by 2 orders of magnitude, thereby producing tensionless bilayers. In addition, we show how to determine, for a certain total number of lipids, the unique spherical vesicle for which both leaflet tensions vanish individually. We also compute the local spontaneous curvature of the spherical membranes by identifying the first moment of the spherically symmetric stress profiles across the lipid bilayers with the nanoscopic torque as derived from curvature elasticity. Our study can be extended to other types of lipid membranes and sheds new light on cellular nanovesicles such as exosomes, which are increasingly used as biomarkers and drug delivery systems.

Bioinspired materials can mimic the stem cell environment and modulate stem cell differentiation and proliferation. In this study, biomimetic micro/nanoenvironments were fabricated by cell-imprinted substrates based on mature human keratinocyte morphological templates. The data obtained from atomic force microscopy and field emission scanning electron microscopy revealed that the keratinocyte-cell-imprinted poly(dimethylsiloxane) casting procedure could imitate the surface morphology of the plasma membrane, ranging from the nanoscale to the macroscale, which may provide the required topographical cell fingerprints to induce differentiation. Gene expression levels of the genes analyzed (involucrin, collagen type I, and keratin 10) together with protein expression data showed that human adipose-derived stem cells (ADSCs) seeded on these cell-imprinted substrates were driven to adopt the specific shape and characteristics of keratinocytes. The observed morphology of the ADSCs grown on the keratinocyte casts was noticeably different from that of stem cells cultivated on the stem-cell-imprinted substrates. Since the shape and geometry of the nucleus could potentially alter the gene expression, we used molecular dynamics to probe the effect of the confining geometry on the chain arrangement of simulated chromatin fibers in the nuclei. The results obtained suggested that induction of mature cell shapes onto stem cells can influence nucleus deformation of the stem cells followed by regulation of target genes. This might pave the way for a reliable, efficient, and cheap approach of controlling stem cell differentiation toward skin cells for wound healing applications.

The response of biomembranes to aqueousphase separation and to the resulting water-in-water droplets has been recently studied on the micrometer scale using optical microscopy and elasticity theory. When such a droplet adheres to the membrane, it forms a contact area that is bounded by a contact line. For a micrometer-sized droplet, the line tension associated with this contact line can usually be ignored compared with the surface tensions. However, for a small nanoscopic droplet, this line tension is expected to affect the membrane-droplet morphology. Here, we use molecular simulations to study nanodroplets at membranes and to gain insight into these line tension effects. The latter effects are shown to depend strongly on another key parameter, the mechanical tension experienced by the membrane. For a large membrane tension, a droplet adhering to the membrane is only partially engulfed by the membrane, and the membrane− droplet system exhibits an axisymmetric morphology. A reduction of the membrane tension leads to an increase in the contact area and a decrease in the interfacial area of the droplet, initially retaining its axisymmetric shape, which implies a circular contact line and a circular membrane neck. However, when the tension falls below a certain threshold value, the system undergoes a morphological transition toward a non-axisymmetric morphology with a non-circular membrane neck. This morphology persists until the nanodroplet is completely engulfed by the membrane and the membrane neck has closed into a tight-lipped shape. The latter morphology is caused by a negative line tension, which is shown to be a robust feature of membrane−droplet systems. A closed membrane neck with a tight-lipped shape suppresses both thermally activated and protein-induced scission of the neck, implying a reduction in the cellular uptake of nanodroplets by pinocytosis and fluid-phase endocytosis. Furthermore, based on our results, we can also draw important conclusions about the time-dependent processes corresponding to the surface nucleation and growth of nanodroplets at membranes.

Membrane budding and fission are essential cellular processes that produce new membrane compartments during cell and organelle division, for intracellular vesicle trafficking as well as during endo-and exocytosis. Such morphological transformations have also been observed for giant lipid vesicles with a size of many micrometers. Here, we report budding and fission processes of lipid nanovesicles with a size below 50 nm. We use coarse-grained molecular dynamics simulations, by which we can visualize the morphological transformations of individual vesicles. The budding and fission processes are induced by low concentrations of small solutes that absorb onto the outer leaflets of the vesicle membranes. In addition to the solute concentration, we identify the solvent conditions as a second key parameter for these processes. For good solvent conditions, the budding of a nanovesicle can be controlled by reducing the vesicle volume for constant solute concentration or by increasing the solute concentration for constant vesicle volume. After the budding process is completed, the budded vesicle consists of two membrane subcompartments which are connected by a closed membrane neck. The budding process is reversible as we demonstrate explicitly by reopening the closed neck. For poor solvent conditions, on the other hand, we observe two unexpected morphological transformations of nanovesicles. Close to the binodal line, at which the aqueous solution undergoes phase separation, the vesicle exhibits recurrent shape changes with closed and open membrane necks, reminiscent of flickering fusion pores (kiss-and-run) as observed for synaptic vesicles. As we approach the binodal line even closer, the recurrent shape changes are truncated by the fission of the membrane neck which leads to the division of the nanovesicle into two daughter vesicles. In this way, our simulations reveal a nanoscale mechanism for the budding and fission of nanovesicles, a mechanism that arises from the interplay between membrane elasticity and solute-mediated membrane adhesion.

During endocytosis of nanoparticles by cells, the cellular membranes engulf the particles, thereby forming a closed membrane neck that subsequently undergoes fission. For solid nanoparticles, these endocytic processes have been studied in some detail. Recently, such processes have also been found for liquid and condensate droplets, both in vitro and in vivo. These processes start with the spreading of the droplet onto the membrane followed by partial or complete engulfment of the droplet. Here, we use molecular dynamics simulations to study these processes at the nanoscale, for nano-sized droplets and vesicles. For both partial and complete engulfment, we observe two different endocytic pathways. Complete engulfment leads to a closed membrane neck which may be formed in a circular or strongly non-circular manner. A closed circular neck undergoes fission, thereby generating two nested daughter vesicles whereas a non-circular neck hinders the fission process. Likewise, partial engulfment of larger droplets leads to open membrane necks which can again have a circular or non-circular shape. Two key parameters identified here for these endocytic pathways are the transbilayer stress asymmetry of the vesicle membrane and the positive or negative line tension of the membrane-droplet contact line.