Steric‐Engineered Thermodynamic Gating: Metastable Assemblies for Chemical‐Class Discrimination of Synthetic Cannabinoids

ABSTRACT Synthetic cannabinoids (SCs), a rapidly evolving class of new psychoactive substances (NPS), trigger severe neurotoxicity and fatalities while evading rapid, structure‐selective on‐site screening. To enable high‐fidelity recognition of such chemically inert targets, we propose a generalizable “Steric‐Engineered Thermodynamic Gating” strategy based on disaggregation‐induced emission (DIE) mechanism that breaks the intrinsic “stability‐sensitivity” deadlock in supramolecular sensing. Distinct from trial‐and‐error optimization, this approach rationally exploits steric bulk to induce active packing frustration, creating metastable aggregates designed to selectively detect SCs via synergistic non‐covalent interactions (e.g., π–π stacking and hydrogen bonding). Functioning as a thermodynamic filter, this assembly remains inert against non‐target interferents yet selectively undergoes cooperative disassembly upon binding with specific SCs via multivalent synergy, transforming a quenched “off” state into a robust blue‐shifted “on” signal. Validating this strategy with EDMB‐PINACA, the system exhibits ultrafast response (