Lipid Self-Assemblies under the Atomic Force Microscope.

Lipid model membranes are important tools in the study of biophysical processes such as lipid self-assembly and lipid-lipid interactions in cell membranes. The use of model systems to adequate and modulate complexity helps in the understanding of many events that occur in cellular membranes, that exhibit a wide variety of components, including lipids of different subfamilies (e.g., phospholipids, sphingolipids, sterols…), in addition to proteins and sugars. The capacity of lipids to segregate by themselves into different phases at the nanoscale (nanodomains) is an intriguing feature that is yet to be fully characterized in vivo due to the proposed transient nature of these domains in living systems. Model lipid membranes, instead, have the advantage of (usually) greater phase stability, together with the possibility of fully controlling the system lipid composition. Atomic force microscopy (AFM) is a powerful tool to detect the presence of meso- and nanodomains in a lipid membrane. It also allows the direct quantification of nanomechanical resistance in each phase present. In this review, we explore the main kinds of lipid assemblies used as model membranes and describe AFM experiments on model membranes. In addition, we discuss how these assemblies have extended our knowledge of membrane biophysics over the last two decades, particularly in issues related to the variability of different model membranes and the impact of supports/cytoskeleton on lipid behavior, such as segregated domain size or bilayer leaflet uncoupling.

Specially-Made Lipid-Based Assemblies for Improving Transmembrane Gene Delivery: Comparison of Basic Amino Acid Residue Rich Periphery.

Cationic lipid based assemblies provide a promising platform for effective gene condensation into nanosized particles, and the peripheral properties of the assemblies are vital for complexation and interaction with physical barriers. Here, we report three cationic twin head lipids, and each of them contains a dioleoyl-glutamate hydrophobic tail and a twin polar head of lysine, arginine, or histidine. Such lipids were proven to self-assemble in aqueous solution with well-defined nanostructures and residual amino-, guanidine-, or imidazole-rich periphery, showing strong buffering capacity and good liquidity. The assemblies with arginine (RL) or lysine (KL) periphery exhibited positive charges (∼+35 mV) and complete condensation of pDNA into nanosized complexes (∼120 nm). In contrast, assemblies composed of histidine-rich lipids (HL) showed relatively low cationic electric potential (∼+10 mV) and poor DNA binding ability. As expected, the designed RL assemblies with guanidine-rich periphery enhanced the in vitro gene transfection up to 190-fold as compared with the golden standard PEI25k and Lipofectamine 2000, especially in the presence of serum. Meanwhile, interaction with cell and endo/lysosome membrane also revealed the superiority of RL complexes, that the guanidine-rich surface efficiently promoted transmembrane process in cellular internalization and endosomal disruption. More importantly, RL complexes also succeeded beyond others in vivo with significantly (∼7-fold) enhanced expression in HepG2 tumor xenografts in mice, as well as stronger green fluorescence protein imaging in isolated tumors and tumor frozen sections.

Lipid Assemblies at the Crossroads of Aging, Proteostasis, and Neurodegeneration.

The proteostasis network (PN) is a nexus of mechanisms that act in concert to maintain the integrity of the proteome. Efficiency of the PN declines with age, resulting in the accumulation of misfolded proteins, and in some cases in the development of neurodegenerative disorders. Thus, maintaining an active and efficient PN through the late stages of life could delay or prevent neurodegeneration. Indeed, altering the activity of aging-regulating pathways protects model organisms from neurodegeneration-linked toxic protein aggregation. Here, we delineate evidence that the formation and integrity of lipid assemblies are affected by aging-regulating pathways, and describe the roles of these structures in proteostasis maintenance. We also highlight future research directions and discuss the possibility that compounds which modulate lipid assemblies could be used for the treatment of neurodegenerative disorders.

Advancing the Pharmaceutical Potential of Bioinorganic Hybrid Lipid-Based Assemblies.

Bioinspired lipid assemblies that mimic the elaborate architecture of natural membranes have fascinated researchers for a long time. These lipid assemblies have gone from being just an imperative platform for biophysical research to a pharmaceutical delivery system for biomedical applications. Despite success, these organized nanosystems are often subject to the mechanical instability and limited theranostic capability without adding any inconvenient modifications. To reach their advanced pharmaceutical potential, various bioinorganic hybrid lipid-based assembles, which provide new opportunities to synergistically complement and improve therapeutic/diagnostic potential of existing lipid-based nanomedicine with distinct mechanisms containing inorganic embedded surfactants, have recently been developed.