2. Academic Validation
  3. Enhanced Accumulation of Heteroduplex Oligonucleotides in Dystrophin-Deficient Skeletal Muscles by Single Oligonucleotide-Loaded Unit Polyion Complexes

Enhanced Accumulation of Heteroduplex Oligonucleotides in Dystrophin-Deficient Skeletal Muscles by Single Oligonucleotide-Loaded Unit Polyion Complexes

  • ACS Omega. 2025 Aug 1;10(31):34363-34371. doi: 10.1021/acsomega.5c02207.
Hiroyuki Chaya 1,  Mitsuru Naito 1,  Kazuko Toh 2 3,  Naoki Yamada 1,  Kaori Taniwaki 1,  Yurugi Kinoshita 1,  Shigeto Fukushima 2,  Katsura Minegishi 4,  Yoshitsugu Aoki 4,  Tetsuya Nagata 3,  Takanori Yokota 3,  Kazunori Kataoka 2,  Kanjiro Miyata 1 5
Affiliations

Affiliations

  • 1 Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
  • 2 Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.
  • 3 Department of Neurology and Neurological Science, Graduate School of Medical and Dental Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
  • 4 Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi-cho, Kodaira, Tokyo 187-8551, Japan.
  • 5 Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
PMID: 40821543 DOI: 10.1021/acsomega.5c02207
Abstract

Efficient delivery of oligonucleotide drugs to muscle tissues remains a significant challenge in nanomedicine and oligonucleotide therapeutics. A primary obstacle is the blood-muscle barrier, a continuous endothelium within muscle tissues that impedes the extravasation of conventional nanomedicines, typically ranging from a few tens of nanometers to 100 nm. To address this challenge, we developed an ultrasmall oligonucleotide nanomedicine, termed the unit polyion complex (uPIC), using a single molecular oligonucleotide with Y-shaped block catiomers. Heteroduplex oligonucleotide (HDO)-loaded uPICs with hydrodynamic diameters of approximately 20 nm were prepared. Comparative analysis revealed that HDO-loaded uPICs accumulated significantly more in the dystrophin-deficient quadriceps of Duchenne muscular dystrophy model (mdx) mice than HDO-loaded lipid nanoparticles (∼90 nm in size). This enhanced accumulation is attributed to superior extravasation and prolonged blood retention of the uPICs. Additionally, the uPICs effectively induced gene knockdown in the quadriceps, highlighting the efficacy of downsizing nanomedicine for overcoming the dystrophin-deficient blood-muscle barrier.

Figures
Products