Aldawod_2025_Nat.Commun_16_686

The opioid crisis, driven by synthetic opioids like fentanyl, demands innovative solutions. The opioid antidote naloxone has a short action ( ~ 1 hour), requiring repeated doses. To address this, we present a new and simple naloxone prodrug delivery system repurposing a hydrophilic derivative of acoramidis, a potent transthyretin ligand. When the fully soluble prodrug solution is administered subcutaneously, the prodrug forms a zwitterionic depot at physiological pH, enabling extended naloxone release. This non-polymeric depot-forming approach is rare and employs carboxylesterase 2 for selective bioactivation, ensuring controlled drug release. In male rats and cynomolgus monkeys, a single subcutaneous dose provides steady naloxone release over several days, reducing blood-brain barrier diffusion, withdrawal symptoms, and CNS toxicity. Preclinical studies demonstrated efficacy in rat overdose models and achieved monkey naloxone levels matching effective human therapeutic levels. Although monkey efficacy was not assessed, combined rat efficacy and monkey pharmacokinetics suggest strong potential for successful human translation.