Precision Adjuvant Design Enabling Tailored Nanoparticle Immunization Platforms for Oxycodone and Other Substance Abuse Vaccines

Abstract

Substance use disorders (SUDs) constitute a growing global health burden, with opioids responsible for nearly two‑thirds of SUD‑related fatalities in the United States. Current pharmacotherapies for opioid use disorder are limited by adherence challenges, diversion risks, and inconsistent efficacy. In contrast, vaccines that elicit antibodies capable of sequestering drug molecules in the peripheral circulation provide a non‑addictive, durable alternative. However, their success hinges on judicious adjuvant selection and optimized antigen delivery. This dissertation integrates systematic adjuvant characterization with nanotechnology‑enabled delivery systems to advance a precision‑vaccinology framework targeting oxycodone and related opioids. A comprehensive analysis of preclinical and clinical literature demonstrated that adjuvant efficacy is drug‑specific. No single formulation suffices across nicotine, stimulant, and opioid antigens. Structural compatibility between adjuvant and delivery system together with synergistic adjuvant combination consistently augments vaccine efficacy, suggesting the significance of empirical formulation tailoring and rational adjuvant design. Building on these insights, in vitro cytometric analyses revealed that interferon‑γ (IFN-γ) efficiently stimulated dendritic cells and, when combined with toll‑like receptor (TLR) 3 or 7/8 agonists, elevated dendritic cell activation from 33 to nearly 60 percent, indicating complementary signaling pathways that potentiated innate immunity. These findings were translated into a modular lipid‑poly(lactic-co-glycolic) acid (PLGA) hybrid nanoparticle (hNP)-based vaccine against oxycodone. Relative to a conventional hapten-carrier conjugate vaccine formulated with aluminum hydroxide, the lipid-PLGA hNP formulation elicited higher anti‑oxycodone antibody titers, enhanced peripheral drug sequestration, and markedly lowered brain oxycodone levels in mice. Subsequent encapsulation of IFN‑γ in combination with the TLR agonists polyinosinic–polycytidylic acid (TLR3 agonist) or resiquimod (TLR7/8 agonist) within the same hNP scaffold yielded the highest serum antibody levels, improved antibody affinity, and the greatest attenuation of brain drug exposure following oxycodone challenge, illustrating the translational value of co‑localized and complementary adjuvants. Collectively, these results demonstrated that rational adjuvant design integrated with scalable nanotechnology can overcome the intrinsically poor immunogenicity of small molecular substances and markedly enhance vaccine performance. This work provides a strategic and technological foundation for next‑generation immunotherapies against oxycodone and other psychoactive substances, complementing existing pharmacological and behavioral interventions to address the ongoing opioid crisis.