Molecular Tailoring of Fluorescent Agents Toward SICTERS-Active Raman Probes.

Self-stacked small molecules relying on the SICTERS mechanism have emerged as a promising platform for ultrasensitive in vivo Raman imaging. However, only a limited number of SICTERS‑active molecules have been reported to date, constraining their broader applications. Herein, we reported a rational strategy to transform conventional fluorophores into SICTERS probes based on two fundamental findings. One is that sulfur-to-selenium substitution is capable of suppressing radiative decay for fluorescence quenching, distinct from its conventional role in red-shifting emission. The other is that N-alkylation enables tuning the absorption profile for Raman enhancement, beyond its traditional use in improving molecular solubility. Mechanistic studies validate these findings. Consequently, a novel SICTERS-active molecule (ATSe) was synthesized from a representative fluorophore (HTS). ATSe exhibited pronounced fluorescence quenching (quantum yield as low as 0.01%) and superior Raman sensitivity (detection limit of 0.014 µg mL-1). ATSe also displayed an exceptional photothermal conversion efficiency of 71.37%, arising from its accelerated nonradiative dissipation. In an orthotopic colon tumor model, ATSe enabled highly effective Raman imaging‑guided photothermal therapy. This work introduces a general method to convert conventional fluorophores into SICTERS probes, opening new avenues for SICTERS‑based biological applications.