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.