A Carfentanil-Targeted Vaccine Adjuvanted with a Covalent TLR7/8 Agonist and a T-Helper Epitope Confers Protective Immunity against Carfentanil-Induced Effects

Carfentanil, an ultrapotent synthetic opioid, poses a severe public health threat because of its rapid brain penetration and potent activation of μ-opioid receptors. Conventional anti-drug vaccines are limited by the poor hapten immunogenicity and dominant anti-carrier immunity. Here, we report a molecularly encoded synthetic carfentanil vaccine (MECVPLA−PEI) integrating a carfentanil hapten, TLR7/8 agonist, and T-helper epitope within a polymeric scaffold to coordinate B and T cell activation. MECVPLA−PEI exhibited markedly enhanced lymph node targeting, with 21.2-fold higher accumulation at 24 h and retention over 7 days, leading to a 1.5-fold increase in plasma cell differentiation and enhanced dendritic cell activation. Compared with an OVA-carrier protein-based vaccine, MECVPLA−PEI induced 22-fold higher antibody titers with a very low level of anti-carrier antibodies and attenuated carfentanil-induced antinociceptive and reward-related behaviors. Importantly, MECVPLA−PEI exhibited a favorable safety profile. This work establishes a precise synthetic vaccine strategy for anti-carfentanil therapy.