Nonviral Vectors for the Delivery of Small Interfering RNAs to the CNS

Inmaculada Posadas; Francisco Javier Guerra; Valentín Ceña


Nanomedicine. 2010;5(8):1219-1236. 

In This Article

Future Perspective

Delivery of genetic material to neurons is one of the therapeutic frontiers in modern medicine. The crossing of this frontier will come from the hand of nanomedicine and, more specifically, from the use of therapeutic NPs, due to problems such as host immune responses and safety concerns resulting from the use of viral vectors. The ability to deliver genes to replace defective or lacking genes during development or immediately after birth will be very relevant to cure or, at least, ameliorate the devastating effects of rare diseases (prevalence of less than five cases/10,000 people) that have a genetic base and, often, delay or preclude the psychomotor development of the affected children.

However, the most spectacular development to come will most likely arise from the use of RNAi technology to selectively inhibit the expression of proteins involved in signaling pathways activated during the development of different diseases, including the more prevalent ones in Western countries, including cancer, cardiovascular and neurodegenerative diseases. In this case, RNAi compounds will be used as therapeutic drugs, leading to new RNAi therapeutics that can interfere with signaling pathways not reachable by traditional drugs.

From the data available at the moment, the most promising NPs to support RNAi therapeutics in the future appear to be dendrimers and carbon nanomaterials, both separately and in combination. In the near future, it should be possible to couple a signaling molecule, a cell-specific targeting group and a therapeutic molecule (either a classical drug or a RNAi 'drug') to the same NP.

However, the development of therapeutic NPs should overcome the current four main problems with their use:

  • Biocompatibility and biodistribution

  • BBB crossing

  • Target-directed delivery

  • Efficient intracellular delivery by effective endosomal escape

Nanoparticle toxicity can be reduced and biocompatibility increased by different functionalization procedures or the coupling of different molecules to the NPs. However, these procedures can modify the biodistribution pattern of the particles that depend upon the particle size, charge and/or attached chemical groups. The combination of these factors can result in retention of the NP by the reticuloendothelial system, thus preventing it from reaching the brain or, on the contrary, resulting in rapid removal from the organism by the kidneys. In order to gain proper information on biodistribution it is important to couple chemical groups suitable for proper NP biodistribution imaging to the NP. Once the biodistribution problem is overcome, BBB crossing should be improved. At present, addition of BBB permeating peptides seems to be the most promising approach, but caution remains in using this approach owing to possible modification to the biodistribution of the original NP.

Specific target delivery of the therapeutic NP is the most challenging task ahead for NP therapeutics. At present, there is almost no information on what proteins are specific and unique in the different types of neurons and glial cells in the CNS, making it difficult to selectively direct a NP to a specific cell type in this system. Achieving this will ideally result in an ideal situation where a therapeutic NP (containing either siRNA or a classical drug) will be target-directed to a specific disease-affected neuronal or glial cell, which will be visualized, at the same time, by the imaging molecule coupled to the NP. However, it would be expected that efficient cellular siRNA delivery by endosomal escape, although still a problem for some NPs, will be efficiently solved since highly efficient in vitro downregulation of specific proteins has already been described in different neuronal types. In addition, CNTs efficiently escape endosomes during cell penetration, suggesting an alternative approach to overcome this problem.

In summary, we will see the development of a new area of therapeutics based on the use of RNAi molecules and its specific target delivery. This will increase our therapeutic armamentarium against several neurological diseases, including neurodegenerative diseases, which presently do not have a curative therapy.


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