Nanodiscs embedded with μ-opioid receptors as decoy receptors to reverse opioid overdose

초록

The clinical reversal of opioid overdose, such as that caused by fentanyl, is achieved using opioid receptor antagonists such as naloxone. While naloxone is lifesaving, its abrupt blockade of μ-opioid receptors (μORs) can precipitate severe acute withdrawal symptoms, partly driven by underlying molecular mechanisms such as receptor desensitization and internalization. In addition, naloxone has a short half-life (30–90 min), requiring repeated administration in cases involving opioids with prolonged pharmacokinetic profiles, such as fentanyl. To address these limitations, we propose a decoy-receptor strategy using μOR-embedded nanodiscs (μOR-NDs) that sequester opioid molecules, thereby attenuating opioid effects without abrupt receptor blockade. μOR-NDs exhibit high in vivo stability and demonstrate brain-associated biodistribution. These results suggest that μOR-NDs can cross the blood–brain barrier (BBB) and have the potential to treat opioid overdose. Overall, this decoy-receptor approach offers an innovative paradigm for safer opioid neutralization with more controlled mitigation of withdrawal. Graphical abstract © 2026 The Authors.

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