IFN-γ and TLR agonist co-adjuvants enhance the efficacy of a lipid-PLGA hybrid nanoparticle-based oxycodone vaccine

The ongoing opioid epidemic continues to drive high rates of substance use disorders (SUD), fatal and non fatal overdoses, with oxycodone being one of the most widely misused prescription opioids. Immunopharmacological strategies such as vaccines that induce drug-specific antibodies offer a non-addictive, long-lasting approach to neutralize opioids in the bloodstream and prevent their entry into the central nervous system (CNS). In this study, we evaluated the immunogenicity and efficacy of novel oxycodone vaccine formulations incorporating interferon-γ (IFN-γ), either alone or in combination with toll-like receptor (TLR) agonists, delivered via either conventional hapten-carrier conjugates or lipid-PLGA hybrid nanoparticles (hNPs). All adjuvanted formulations elicited robust anti-oxycodone IgG responses, with IFN-γ + TLR agonist combinations particularly in the hNP platform producing the highest titers and enhanced antibody affinity. Subclass analysis, performed on the hNP-based vaccines, revealed IgG1-dominant responses, with modest IgG2a induction in the TLR-adjuvanted groups, suggesting partial Th1 skewing. Pharmacokinetic studies showed significantly elevated serum and reduced brain oxycodone levels in all vaccinated animals, with the hNP-based vaccine adjuvanted with IFN-γ and R848 providing the most potent CNS protection. In the hot plate assay, all formulations significantly attenuated oxycodone-induced antinociception, with the hNP-based vaccine formulated with IFN-γ and poly I:C producing the greatest reduction. These findings demonstrate that co-delivery of IFN-γ and a TLR agonist via a nanoparticle platform enhances both the magnitude and functional quality of the immune response, supporting further development of this strategy as a promising therapeutic approach for opioid use disorder.