The abusive use of opioid prescription drugs, often referred to as ‘the opioid crisis, has become a major global problem facing an exuberant number of deaths. To tackle this tremendous challenges, anti-opioid immunotherapy is considered as a promising therapy. The current generation of anti-opioid vaccines are based on random covalent conjugation of opioid haptens to a carrier protein in combination with an admixed adjuvant, and most likely do not fully embrace the potential of anti-opioid immunotherapy due to immunodominance of the carrier protein, sub-optimal priming of the immune system and translational challenges due to difficulties to reproduce and characterize hapten-protein conjugates. Focusing on fentanyl as a prominent opioid of concern, we present in this proposal a more rational anti-opioid vaccine design based on a non-covalent assembly of opioid haptens, T-helper epitope and an immune-stimulant into a single lipid nanoparticle (LNP). The latter is engineered for optimal delivery to secondary lymphoid organs and to mediate multivalent hapten ligand exposure on a spherical nanoparticle template for optimal induction of hapten-specific antibody responses. In this project we will explore both peptide and mRNA as a format for the requited T-helper epitope and will investigate how LNP design affects the amplitude and quality of the anti-opioid immune response and whether this confers protection in pre-clinical mouse models against opioid overdosing.