Molecular Engineering of a SICTERS Small Molecule with Superior <i>In Vivo</i> Raman Imaging and Photothermal Performance

Raman-based theranostics has demonstrated great potential for sensitive real-time imaging and treatment. However, these advanced materials, primarily depending on the SERS technique, encounter clinical concerns regarding substrate biosafety. Herein, we molecularly engineered a <i>de novo</i> substrate-free SICTERS small molecule, namely BTT-TPA (bis-thienyl-substituted benzotriazole selenadiazole derivative structures), possessing both ultrasensitive Raman signals and excellent photothermal effects based on self-stacking. The mechanistic studies confirm that BTT maintains the planar structure with polycyclic distorted vibrations required for SICTERS. TPA enhances the donor-acceptor interaction, yielding a Raman sensitivity of BTT higher than previously reported SICTERS molecules; it also acts as a molecular rotor, increasing the photothermal conversion efficiency to 67.44%, which is superior to most of the existing SERS-based photothermal materials. In the tumor model of mouse orthotopic colon cancer, BTT-TPA NPs demonstrate a great Raman imaging-guided photothermal therapy effect in eliminating primary and metastatic tumors, remarkably decreasing the recurrence rate. This work puts forward substrate-free SICTERS small molecules toward Raman-based theranostic applications <i>in vivo</i>.