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<p>Nucleic acid aptamers are promising next-generation experimental and therapeutic drugs for uncharacterized biomolecules and intractable diseases. However, efficient aptamer selection remains challenging. We have developed a functional selection method termed extracellular vesicle (EV)-SELEX that efficiently selects DNA aptamers for G protein-coupled receptors (GPCRs), a major class of drug targets via ligand-dependent GPCR endocytosis and subsequent release of GPCR-containing EVs. Using this method, we obtained Dapt-μR, a DNA aptamer that had a high affinity to μ-opioid receptor (MOR) (K<sub>d</sub> ≈ 28 nM) but no other types of opioid receptors. In unmodified form, Dapt-μR acted as a morphine-like, naloxone-sensitive MOR agonist, inhibiting cAMP accumulation in cultured cells and reducing Ca<sup>2+</sup> influx in primary striatal neurons. Furthermore, Dapt-μR selectively bound to the MOR-rich spinal cord dorsal horn and produced an analgesic effect following intrathecal administration in mice. These findings demonstrate that EV-SELEX is a powerful method for selecting DNA aptamers for target GPCRs.</p>

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Efficient and specific selection of high-affinity DNA aptamers targeting μ-opioid receptor via functional extracellular vesicles

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月7日

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  • Mitsushi J. Ikemoto,
  • Yuji Kamikubo,
  • Daisuke Uta,
  • Kengo Kirinoki,
  • Mari Kiriyama,
  • Takumi Miyajima,
  • Hakushun Sakairi,
  • Masanobu Kano,
  • Takashi Sakurai,
  • Toshihide Tabata

摘要

Nucleic acid aptamers are promising next-generation experimental and therapeutic drugs for uncharacterized biomolecules and intractable diseases. However, efficient aptamer selection remains challenging. We have developed a functional selection method termed extracellular vesicle (EV)-SELEX that efficiently selects DNA aptamers for G protein-coupled receptors (GPCRs), a major class of drug targets via ligand-dependent GPCR endocytosis and subsequent release of GPCR-containing EVs. Using this method, we obtained Dapt-μR, a DNA aptamer that had a high affinity to μ-opioid receptor (MOR) (Kd ≈ 28 nM) but no other types of opioid receptors. In unmodified form, Dapt-μR acted as a morphine-like, naloxone-sensitive MOR agonist, inhibiting cAMP accumulation in cultured cells and reducing Ca2+ influx in primary striatal neurons. Furthermore, Dapt-μR selectively bound to the MOR-rich spinal cord dorsal horn and produced an analgesic effect following intrathecal administration in mice. These findings demonstrate that EV-SELEX is a powerful method for selecting DNA aptamers for target GPCRs.