Successful cytosolic delivery of nanomaterials is becoming more and more important, given the increase in intracellular applications of quantum dots, gold nanoparticles, liposomal drug formulations and polymeric gene delivery vectors. Most nanomaterials are taken up by the cell via endocytosis, yet endosomal escape has long been recognized as a major bottleneck in cytosolic delivery. Although it is essential to detect and reliably quantify endosomal escape, no consensus has been reached so far on the methods to do so. This review will summarize and discuss for the first time the different assays used to investigate this elusive step to date.

Therapeutic application of nucleic acids requires their encapsulation in nanosized carriers that enable safe and efficient intracellular delivery. Before the desired site of action is reached, drug-loaded nanoparticles (nanomedicines) encounter numerous extra- and intracellular barriers. Judicious nanocarrier design is highly needed to stimulate nucleic acid delivery across these barriers and maximize the therapeutic benefit. Natural polysaccharides are widely used for biomedical and pharmaceutical applications due to their inherent biocompatibility. At present, there is a growing interest in applying these biopolymers for the development of nanomedicines. This review highlights various polysaccharides and their derivatives, currently employed in the design of nucleic acid nanocarriers. In particular, recent progress made in polysaccharide-assisted nucleic acid delivery is summarized and the specific benefits that polysaccharides might offer to improve the delivery process are critically discussed.

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An ex vivo eye model is presented for studying nanoparticle mobility in intact vitreous humor by single-particle tracking microscopy. These results give important guidelines for developing gene- and drug-delivery nanomedicines that are compatible with intravitreal administration.

This study describes a novel liposomal formulation for siRNA delivery, based on the mixture of the neutral lipid monoolein (MO) and cationic lipids of the dioctadecyldimethylammonium (DODA) family. The cationic lipids dioctadecyldimethylammonium bromide (DODAB) and chloride (DODAC) were compared in order to identify which one will most efficiently induce gene silencing. MO has a fluidizing effect on DODAC and DODAB liposomes, although it was more homogeneously distributed in DODAC bilayers. All MO-based liposomal formulations were able to efficiently encapsulate siRNA. Stable lipoplexes of small size (100-160 nm) with a positive surface charge (>+45 mV) were formed. A more uniform MO incorporation in DODAC:MO may explain an increase of the fusogenic potential of these liposomes. The siRNA-lipoplexes were readily internalized by human nonsmall cell lung carcinoma (H1299) cells, in an energy dependent process. DODAB:MO nanocarriers showed a higher internalization efficiency in comparison to DODAC:MO lipoplexes, and were also more efficient in promoting gene silencing. MO had a similar gene silencing ability as the commonly used helper lipid 1,2-dioleyl-3-phosphatidylethanolamine (DOPE), but with much lower cytotoxicity. Taking in consideration all the results presented, DODAB:MO liposomes are the most promising tested formulation for systemic siRNA delivery.

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