Redefining Drug Immune Recognition: A Radically Reconfigured Molecular Architecture Enables Broad Fentanyl-Class Protection

Synthetic opioids pose a chemically evolvable threat, in which extreme potency and rapid diversification allow fentanyl analogues to outpace structure-specific countermeasures. Immune strategies largely responded by copying the parent chemotype, implicitly treating small-molecule recognition as scaffold-dependent. Here, we examined an alternative hypothesis: adaptive immunity can recover fentanyl-class identity from transferable spatial and physicochemical information. Replacing the canonical piperidine of fentanyl with a 2-azaspiro[3.3]heptane, we created a chemically orthogonal immunogen with a radically altered three-dimensional arrangement. Despite this, vaccination elicited high-titer cross-reactive antibodies, broad fentanyl-analogue binding, and protection matching a fentanyl-derived benchmark. Fentanyl antinociception shifted into the ∼1.1–2.1 mg kg –1 range, preserved ventilation during respiratory challenge, and reduced brain fentanyl from 61.9 ± 10.0 to 17.2 ± 0.7 nM. These results reveal programmable antibody recognition, demonstrating that molecular class identity arises not from direct structural mimicry but through higher-order spatial and physicochemical relationships.