Opioids have significant adverse effects highlighted by the large number of patients with opioid use disorder (OUD) and the increasing number of overdose deaths in the United States and elsewhere. In just the 12-month period ending in November 2021, more than 107,000 Americans died from drug overdose. Around 66% of these deaths involved illicit synthetic opioids like fentanyl (approximately 50 times more potent than heroin and 100 times more potent than morphine), which is the primary driver of the opioid epidemic today. Many of the opioid overdose deaths are attributed to fentanyl mixed with other illicit drugs like heroin, cocaine, and methamphetamine. The potential lethal dose of fentanyl is around two milligrams, and it is particularly dangerous for opioid naïve people who do not have a tolerance to opioids. Overdose deaths among high school-aged Americans have more than doubled since 2019, which has been attributed to counterfeit pills (e.g., Xanax, Percocet, Adderall) laced with a lethal amount of fentanyl. Sadly, many users often ingest the deadly drug unknowingly. Unfortunately, there is not a happy ending for this devastating story and there is no easy solution to the synthetic opioid problem. The vulnerability of our nation to the weaponization of highly potent fentanyl analogs, such as carfentanil (20-fold more potent than fentanyl), poses a significant public health risk not only to civilians, but also to first responders, law enforcement personnel, and the military. The relatively short duration of action (DOA) of the mu-opioid receptor antagonists, naloxone and nalmefene, poses a major challenge for its efficacy against fentanyl overdose. It is difficult to imagine how naloxone and nalmefene could be deployed effectively in a mass casualty situation involving synthetic opioids (where duration of overdose could last up to 24 hr). The overall goal of this proposal is to develop a fundamentally novel drug delivery approach for extending the DOA of current