Engineered Substrate‐Free Small Molecules for Enhanced Raman Scattering and Photothermal Conversion Efficiency

Raman spectroscopy with surface-enhanced Raman scattering (SERS) through metal substrates is a highly precise bioimaging technique. Alternatively, recently discovered small molecules to enhance the Raman signal intensities through their self-stacking, termed stacking-induced intermolecular charge transfer-enhanced Raman scattering (SICTERS), offer ultrasensitive in vivo Raman imaging free of substrates. Molecular engineering to increase the SICTERS intensity and to tune photothermal conversion efficiency of these molecules is critical for furthering their biomedical application but not yet feasible. Here, by increasing the length of side chain and introducing the benzene ring to bis-thienyl-substituted benzobisthiadiazole, this study demonstrates an optimized molecule BBTPPRO that possesses both high SICTERS intensity and photothermal conversion efficiency (31.19%). The prepared BBTPPRO nanoparticles achieve intraoperative Raman image-guided photothermal therapy (PTT) of orthotopic mouse colon tumor. Overall, this report presents a molecular strategy combing the principle of SICTERS with the Jablonski diagram to design substrate-free Raman small molecules toward SICTERS-mediated photo-theranostic agents.