Soft Nanostructured Films for Actuated Surface‐Based siRNA Delivery

Abstract

Substrate-mediated gene delivery is an emerging technology that enables spatial control of gene expression and localized delivery. This is of particular interest for siRNA where surface-based delivery methods could greatly impact the fields of stem-cell reprograming, wound healing, and medical device coatings in general. However, reports on the use of siRNA for substratemediated delivery are scarce and have suffered from low efficiency. Here, we report an alternative strategy by designing self-assembled substrates that experience stimuli-responsive topological transformations. Specifically, we established a methodology to promote the molecular organization of lipid films having 3D-bicontinuous cubic, 2D-inverted hexagonal, or 1D-lamellar nanostructures encapsulating siRNA. In response to a compositional, temperature, or humidity stimulus the nanostructures evolve from 1D-lamellar to 3D-cubic resulting in efficient siRNA release to human cell cultures. Grazing Incidence X-ray Diffraction reveals that film nanostructures are highly ordered and preferentially aligned. Our results indicate that film structure substantially affects siRNA delivery, with the supported 3D-bicontinuous cubic phase yielding the most effective reduction of gene expression. Subsequent studies suggest this enhanced performance arises due to the ability of this phase to cross cell membranes, particularly those of endocytic compartments. Our work underpins that nanostructure tuning is decisive to the performance of therapeutic films.

Nature‐Inspired Design and Application of Lipidic Lyotropic Liquid Crystals

“…The authors also showed that the hexagonal mesophases were more effective at gene silencing compared to their lamellar structured counterparts. More recently, Kang and Leal have shown that using the same electrostatic strategy proposed by Amar‐Yuli et al and Zhen et al siRNA can be encapsulated not only in inverse columnar hexagonal mesophases, but also within inverse bicontinuous cubic mesophases …”

Cubosomes: The Next Generation of Smart Lipid Nanoparticles?

“…This has been demonstrated in nanoparticles [45] and as an adsorbed thin film in the gyroid cubic phase for surface based nucleic acid delivery. [118] The inclusion of DOTAP and subsequent loading with nucleic acids can alter the cubosome phase morphology and lead to formation of the hexagonal phase or 'hexosomes' as they are referred to in particulate form. [119,120] There is a review specifically focusing on how nucleic acids can self-organize upon loading into lipid constructs such as cubosomes.…”

Graphene-based sensing of oxygen transport through pulmonary membranes

“…In this respect, it is imperative to obtain uniform lung membrane film thickness. We have shown that lipid film thickness, even for complex mixtures, can be controlled by spin-coating speed [45][46][47] . The thickness and morphology of lung membranes can be determined by AFM using the tip-scratch method (Fig.…”

“…Bicontinuous cubic phases (Q II ) are highly porous comprising a continuum hydrophobic membrane intercalated by continuous water channels. Glycerol monooleate (GMO), and 1,2-dioleoyl-3-trimethylammonium-propane chloride salt (DOTAP) at 85:15 molar ratios form bicontinuous cubic structures of the gyroid type (Q G II ) in the form of lipid films when equilibrated at 100% RH 45 . As shown in the X-ray diffraction pattern ( Supplementary Fig.…”