As I understand it, the toxicity is caused by the implementation of the LNP delivery system, rather than a factor inherent to LNP delivery in general. As there

As I understand it, the toxicity is caused by the implementation of the LNP delivery system, rather than a factor inherent to LNP delivery in general. As there are LNP systems that have proven to effectively deliver to target. Basically, this LNP delivery system is for encapsulating a desired portion of RNA within a 'shell'[+], so that it may be delivered to a biological target. The shell is necessary because siRNA is anionic and hydrophilic (negatively charged and water loving/binding.) Which makes it difficult to deliver to targets. It is also unstable in serum (component of blood) and can have unintended side effects if delivered to the wrong target. There have been attempts to engineer custom siRNA directly. These attempts have resulted in siRNA that cause fewer unintended side effects and have higher stability. However, this method still requires high dosage in vivo and the effects are limited to the liver. The more promising approach involves wrapping the siRNA in a lipid 'shell'. The 'shell' is inserted into the biological system and travels through the bloodstream to the target area. The two underlying causes of toxicity (in some LNP delivery implementations) seem to be: the charge of the LNP system and the 'dosage' of the LNP delivery system. Recent research has shown that it is possible to engineer these 'shells' in such a fashion that they can carry the siRNA safely to target, mitigate the undesirable surface charge, and require relatively low dosage. Specifically, they have developed ionizable cationic lipids with pKa below 7 to encapsulate the 'package' at a low pH, while maintaining a relatively neutral surface charge at physiological pH. Also, the delivery 'package' itself is made much smaller. ([+] Lipid Nanoparticle delivery is a means of biological/in-solution transport for small matter in general, in this case it is specifically a means of delivering small interface RNA, siRNA, within a biological system.) Disclaimer: I'm not an expert, but I do have experience in a somewhat related field. This is a high level explanation and it's possible that my explanation handwaves or is mistaken in some aspect. These papers do a better job of explaining it than I can: http://www.ncbi.nlm.nih.gov/pubmed/21179008 http://www.ncbi.nlm.nih.gov/pubmed/21179008 http://www.liposomes.ca/publications/311%20Wan%20et%20al%202013.pdf http://www.liposomes.ca/publications/311%20Wan%20et%20al%202...