Project Summary Substance use disorder (SUD) is a major health concern and currently there are no FDA-approved treatments for cocaine, methamphetamine, and cannabis dependence. Although many molecular targets have been identified in animal models of SUD, the ability to deliver therapeutic agents to the brain and specific brain cells remains a significant challenge. For progress to be made in SUD treatments, new technologies are needed that safely and effectively deliver both small and large molecules to targeted brain cells over a sustained interval. Recently, we developed and optimized block co-polymers of Poly lactic acid (PLA) and hyper-branched polyglycerol (PLA-HPG) nanoparticle (NP) formulations. This new class of non-toxic, bio-compatible NPs has several advantages over traditional NPs for brain targeted therapeutic delivery, including: smaller size for effective brain penetration, resistance to protein adsorption/cell adhesion, sustained delivery of diverse payloads for serval days, and modifiable surfaces for targeted delivery. In the proposed studies, we aim to further assess the safety, bio-distribution, and effectiveness of PLA-HPG NP-mediated therapeutic delivery in animal models of compulsive cocaine intake. Since identification of novel nano-delivery systems for cocaine use disorder is highly innovative and potentially of high impact, this proposal is especially pertinent for the “Step Up for Substance Use Disorders (SUD)” initiative. Furthermore, results from these initial studies may stimulate future experiments that examine PLA-HPG NPs for cell type-specific therapeutic delivery within the brain.