Abstract
Two decades since the discovery of the RNA interference (RNAi) pathway, we are now witnessing the approval of the first RNAi-based treatments with small interfering RNA (siRNA) drugs. Nevertheless, the widespread use of siRNA is limited by various extra- and intracellular barriers, requiring its encapsulation in a suitable (nanosized) delivery system. On the intracellular level, the endosomal membrane is a major barrier following endocytosis of siRNA-loaded nanoparticles in target cells and innovative materials to promote cytosolic siRNA delivery are highly sought after. We previously identified the endogenous lung surfactant protein B (SP-B) as siRNA delivery enhancer when reconstituted in (proteo) lipid-coated nanogels. It is known that the surface-active function of SP-B in the lung is influenced by the lipid composition of the lung surfactant. Here, we investigated the role of the lipid component on the siRNA delivery-promoting activity of SP-B proteolipid-coated nanogels in more detail. Our results clearly indicate that SP-B prefers fluid membranes with cholesterol not exceeding physiological levels. In addition, SP-B retains its activity in the presence of different classes of anionic lipids. In contrast, comparable fractions of SP-B did not promote the siRNA delivery potential of DOTAP:DOPE cationic liposomes. Finally, we demonstrate that the beneficial effect of lung surfactant on siRNA delivery is not limited to lung-related cell types, providing broader therapeutic opportunities in other tissues as well.
Highlights
Over the last two decades, research in the field of RNA interference (RNAi) therapeutics has gained attention as it allows to address diseases at the transcriptome level [1]
Earlier work has demonstrated improved small interfering RNA (siRNA) delivery and targeted gene silencing with Pulmonary Surfactant (PS)-coated nanocomposites in both non-small cell lung cancer cells (H1299) and alveolar macrophages [21,24,25]
To evaluate if PS can likewise promote siRNA delivery in cell lines derived from other organs, human ovarian carcinoma cells (SKOV-3) and human hepatoma cells (Huh-7) were treated with CS-coated siRNA-loaded nanogels (siNGs) (Figure 2e–h)
Summary
Over the last two decades, research in the field of RNAi therapeutics has gained attention as it allows to address diseases at the transcriptome level [1] Once they reached the cytosol, small interfering RNAs (siRNAs) activate the RNAi machinery, leading to post-transcriptional gene silencing through sequence-specific degradation of mRNA [2,3]. High target specificity and versatility of this emerging class of therapeutics represent some of the main advantages compared to conventional small molecule drugs and monoclonal antibodies, providing a wide range of biomedical uses [1,3] Their application in the clinic is limited by many extra- and intracellular delivery barriers. Our earlier data suggest that the type of lipid with which the SP-B is associated, can influence its siRNA delivery efficiency. We sought to reconstitute the cationic amphiphilic SP-B in DOTAP:DOPE cationic liposomes with the aim to promote their cellular siRNA delivery efficiency
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