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Recently, the number of gene and oligonucleotide drugs are increasing. Of various drug delivery systems (DDSs) for gene and oligonucleotide drugs, few examples of the clinical application of polymer as drug carriers are known, despite development of the novel polymers has been progressing. Cyclodextrin (CD) conjugates with starburst polyamidoamine (PAMAM) dendrimer (CDEs), as a new type of polymer-based carriers, were first published in 2001. After that, galactose-, lactose-, mannose-, fucose-, folate-, and polyethyleneglycol (PEG)-appended CDEs have been prepared for passive and active targeting for gene, oligonucleotide, and low-molecular-weight drugs. PEG-appended CDE formed polypsuedorotaxanes with α-CD and γ-CD, which are useful for a sustained release system of gene and oligonucleotide drugs. Interestingly, CDEs were found to have anti-inflammatory effects and anti-amyloid effects themselves, which have potential as active pharmaceutical ingredients. Most recently, CDE is reported to be a useful Cas9-RNA ribonucleoproteins (Cas9 RNP) carrier that induces genome editing in the neuron and brain. In this review, the history and progression of CDEs are overviewed. [ABSTRACT FROM AUTHOR]

The world-first success of lipid nanoparticle (LNP)-based siRNA therapeutics (ONPATTRO®) promises to accelerate developments in siRNA therapeutics/gene therapy using LNP-type drug delivery systems (DDS). In this study, we explore the optimal composition of an LNP containing a self-degradable material (ssPalmO-Phe) for the delivery of oligonucleotides. siRNA or antisense oligonucleotides (ASO) were encapsulated in LNP with different lipid compositions. The hepatic knockdown efficiency of the target genes and liver toxicity were evaluated. The optimal compositions for the siRNA were different from those for ASO, and different from those for mRNA that were reported in a previous study. Extracellular stability, endosomal escape and cellular uptake appear to be the key processes for the successful delivery of mRNA, siRNA and ASO, respectively. Moreover, the compositions of the LNPs likely contribute to their toxicity. The lipid composition of the LNP needs to be optimized depending on the type of nucleic acids under consideration if the applications of LNPs are to be further expanded. [ABSTRACT FROM AUTHOR]