4.4 Article

Delivery of therapeutic oligonucleotides targeting Dectin-1 using quantized complexes

Journal

POLYMER JOURNAL
Volume 54, Issue 4, Pages 591-601

Publisher

SPRINGERNATURE
DOI: 10.1038/s41428-021-00595-8

Keywords

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Funding

  1. JST CREST
  2. JSPS KAKENHI [20H00668, 20K20449]
  3. Grants-in-Aid for Scientific Research [20H00668, 20K20449] Funding Source: KAKEN

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This paper introduces a new quantized complex that has the ability to accurately control the quantity of AS-ODNs, and is more easily taken up by cells compared to conventional complexes, thus providing higher efficiency in antisense therapy.
Finding an appropriate carrier for antisense oligonucleotides (AS-ODNs) and improving the efficiency of their delivery to cells and organs has been critical for the translation of antisense therapy into practice for more than 30 years. We have used a beta-glucan, schizophyllan (SPG), as a delivery tool to solve this issue. SPG forms a complex with AS-ODNs that can be taken up by cells expressing the beta-glucan receptor Dectin-1. We used SPG/AS-DNA complexes containing four to ten ODNs with a relatively large distribution of molecular weights. We recently discovered a complex in which the number of AS-ODNs can be accurately controlled and denoted it as a quantized complex. Building on our previous work, this paper presents the biological properties of this new quantized complex, including its efficacy for cells expressing Dectin-1 and the mechanism behind its cellular uptake of gene-silenced AS-ODNs and immunostimulatory CpG-ODNs. We found that this new complex is also recognized by Dectin-1, and interestingly, is more effective than the conventional complexes, owing to its easier escape from the endocytotic pathway.

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