Vitoria Simas*, Nick Manicke, and Rajesh Sardar | Indiana University–Purdue University Indianapolis Abstract: Nationally, the Centers for Disease Control and Prevention (CDC) reports that from March 2020 through April 2021 nearly 101,000 people died from drug overdoses, the largest number of drug overdoses for a 12-month period ever recorded, including 1150 adolescents.1 The epidemic has accelerated during the COVID-19 pandemic. The CDC reports between 38%–50% increases in opioid overdoses in 28 states.2 Such dismal statistics impose ever greater challenges for criminal justice and drug analysis in forensic toxicology. Liquid chromatography–mass spectrometry (LC–MS) is the gold standard for analysis, but this technique is labor- and time-intensive and has proven too complex to implement in local toxicology laboratories. Consequently, serious backlogs have emerged nationally across jurisdictions. Herein, we demonstrate uniquely shaped gold nanostructures in the fabrication of a new nanoparticle (NP)-decorated microneedle array, which functions as both a highly sensitive surface-enhanced Raman spectroscopy (SERS) substrate for Raman analysis and an efficient sample preparation and ionization device for substrate-supported electrospray ionization–mass spectrometry (ssESI-MS). SERS analysis provides a unique spectroscopic fingerprint for each drug, with signal strength correlated to concentration. Electrospray MS is faster and less labor-intensive than LC–MS, with near equivalent specificity and selectivity. Together, SERS and ssESI-MS are orthogonal and complementary techniques, the combination of which is highly specific and able to unambiguously identify a large majority of potent drugs. The array also enables high-throughput toxicology drug analysis by SERS and MS simultaneously without the need for offline sample preparation. Together, multimodal SERS-ssESI-MS analysis enhances the specificity and selectivity compared to LC–MS in forensic toxicology. Therefore, we expect that this method would be suitable for implementation for high-throughput drug analysis in local forensic laboratories nationwide to battle the drug overdose epidemic. References 1. Centers for Disease Control and Prevention. “Overdose Deaths Accelerating During COVID-19.” (2020) CDC Newsroom. December 18, 2020.https://www.cdc.gov/media/releases/2020/p1218-overdose-deaths-covid-19.html. https://nam04.safelinks.protection.outlook.com/?url=https://www.cdc.gov/media/releases/2020/p1218-overdose-deaths-covid-19.html&data=05|01|jmckay@rti.org|99b91c2b3f7747e027be08dadd4bd104|2ffc2ede4d4449948082487341fa43fb|0|0|638065614941218117|Unknown|TWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0=|3000|||&sdata=rUF8viRve9QQxGvMWAMKNg3qukrf9CesPCnuizCGsSc=&reserved=0 2. Centers for Disease Control and Prevention. “Increase in Fatal Drug Overdoses Across the United States Driven by Synthetic Opioids Before and During the COVID-19 Pandemic.” Emergency Preparedness and Response. December 17, 2020. https://emergency.cdc.gov/han/2020/han00438.asp.