Supermolecule-engineered nanogap hotspots: Ultra-selective and sensitive SERS detection and intracellular imaging

The selective detection of weakly adsorbing, low-abundance molecules in complex biological environments remains a fundamental limitation of conventional surface-enhanced Raman scattering (SERS) technology. Here, we engineered a macrocyclic supramolecular pillararene-bridged gold nanoparticle assembly to create sub-nanometer plasmonic gaps with intense electromagnetic hotspots, enabling ultrasensitive molecule detection in complex matrix. The pillararene-functionalized interface not only enhanced SERS signals (with enhancement factor of 1.3 × 10 7 for curcumin, a model phenolic drug), but also provided selective recognition of phenolic biomarkers through host–guest chemistry, effectively suppressing background noise in water, cell lysate and serum environments. Combined with single-molecule counting, the detection limit reached to 1.03 × 10 −12  mol/L for curcumin. Cellular imaging experiments demonstrated that the pillararene linker facilitated intracellular delivery of curcumin while simultaneously amplifying its Raman signal, enabling real-time tracking of drug distribution at subcellular resolution. This work establishes a versatile detecting platform that integrates supramolecular targeting with plasmonic enhancement, advancing spatially resolved detection of low-abundance molecules in complex biological environments for precision diagnostics and therapeutic evaluation.