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Fentanyl\u2010specific immunotherapy, which aims at inducing fentanyl\u2010specific antibodies capable of binding fentanyl molecules in the bloodstream, preventing their entry in the central nervous system, is therefore gaining momentum. Conventional opioid designs rely on the covalent conjugation of fentanyl analogues to immunogenic carrier proteins that hold the inherent capacity of mounting immunodominant responses. Here, we present an alternative fentanyl vaccine design that utilizes a non\u2010covalent assembly of lipid nanoparticles (LNPs) to deliver fentanyl haptens in conjunction with a CD4<jats:sup>+<\/jats:sup> T\u2010helper peptide epitope and an imidazoquinoline TLR7\/8 agonist. Our results demonstrate that a single intramuscular administration of the LNP\u2010based nanovaccine elicits fentanyl\u2010specific antibodies, significantly mitigating the effects of opioid overdose in preclinical mouse models. Furthermore, we analyzed the immunobiological behavior of the vaccine in vivo in mouse models, providing evidence that covalent attachment of a fentanyl hapten to a carrier proteins or peptide epitope is not necessary for inducing an effective immune response. However, co\u2010delivery \u2010 specifically, the physical assembly of all immune cues into an LNP \u2010 remains essential for inducing hapten\u2010specific immunity.<\/jats:p>","DOI":"10.1002\/anie.202419031","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T13:25:17Z","timestamp":1729689917000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A Fentanyl Hapten\u2010Displaying Lipid Nanoparticle Vaccine that Non\u2010Covalently Encapsulates a TLR7\/8 Agonist and T\u2010Helper Epitope Induces Protective Anti\u2010Fentanyl Immunity"],"prefix":"10.1002","volume":"64","author":[{"given":"Zifu","family":"Zhong","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics Ghent University, Belgium  Ottergemsesteenweg 460 Gent 9000 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