Project Summary/Abstract Over 400 million adults worldwide are living with Type 2 diabetes (T2D). Despite significant advancements in effective treatments, T2D continues to rise at a concerning rate, and by 2035 it is projected that there will be >590 million patients diagnosed globally with this condition- making it one of the costliest chronic health conditions for patients and society. Glucagon-like peptide-1 receptor agonists (GLP- 1 RA) have revolutionized the treatment of T2D because they provide substantial reductions in HbA1c as well as addressing the underlying metabolic dysfunction of obesity that both can cause and complicate the management of diabetes. Regimens that provide sustained plasma levels of GLP-1 RA provide optimal therapeutic effects and this has led to the development of formulations and/or modifications of the native sequence aimed at extending the peptide half-life. Semaglutide is a long acting GLP-1 analogue with low renal clearance and a long elimination half-life. This is achieved by engineering the peptide to avoid renal clearance and enzymatic degradation. While these modifications have reduced treatment frequency from daily to weekly, poor adherence linked to perceived treatment complexity and needle fear remains a general problem. These barriers highlight the critical need for new modes of GLP-1 RA delivery. This proposal seeks to address these limitations by exploring use of the MIMIXTM platform to enable simple and effective GLP-1 RA delivery. The MIMIX platform is a clinically demonstrated, novel microneedle array patch (MAP) characterized by slowly dissolving microneedle tips that ‘deploy’ into the dermis following patch application. The platform further utilizes novel excipients such as silk fibroin to stabilize and support sustained release of therapeutics and vaccines from the deployed tips. The shelf stability achieved with this platform could enable MIMIX devices to be shipped through standard mail to enable self-application. The potential for a sustained release formulation could reduce treatment frequency. Additionally, the MIMIX MAP is delivered using a spring-loaded applicator, a feature that will simplify perception of treatment complexity. In sum, we hypothesize that the MIMIX platform can be a new mode of GLP-1 RA delivery that is 1) needle free to address the treatment hesitancy associated with needle avoidance 2) shelf stable to facilitate home delivery and storage and 3) applied with a spring-loaded applicator to enable self-application. These features will enhance the patient experience and help to improve adherence to treatment. Our preliminary work has demonstrated good compatibility of the GLP-1 RA, semaglutide, with the MIMIX production process. Successful completion of the activities in this proposal will build on these results and will form the initial steps towards identification of lead candidates for further development with the ultimate goal of developing a product that reduces the gl...