Raman spectroscopy using surface-enhanced Raman scattering (SERS) nanoprobes represents an ultrasensitive and high-precision technique for in vivo imaging. Clinical translation of SERS nanoprobes has been hampered by biosafety concerns about the metal substrates used to enhance Raman signals. We report a set of small molecules with bis-thienyl-substituted benzobisthiadiazole structures that enhance Raman signal through self-stacking rather than external substrates. In our technique, called stacking-induced charge transfer-enhanced Raman scattering (SICTERS), the self-stacked small molecules form an ordered spatial arrangement that enables three-dimensional charge transfer between neighboring molecules. The Raman scattering cross-section of SICTERS nanoprobes is 1350 times higher than that of conventional SERS gold nanoprobes of similar particle size. SICTERS outperforms SERS in terms of in vivo imaging sensitivity, resolution and depth. SICTERS is capable of noninvasive Raman imaging of blood and lymphatic vasculatures, which has not been achieved by SERS. SICTERS represents an alternative technique to enhance Raman scattering for guiding the design of ultrasensitive substrate-free Raman imaging probes.

使用表面增强拉曼散射 (SERS) 纳米探针的拉曼光谱代表了一种超灵敏、高精度的体内成像技术。由于对用于增强拉曼信号的金属基底的生物安全性担忧，SERS 纳米探针的临床转化受到阻碍。我们报告了一组具有双噻吩基取代的苯并双噻二唑结构的小分子，它们通过自堆积而不是外部底物增强拉曼信号。在我们的技术中，称为堆叠诱导电荷转移增强拉曼散射（SICTERS），自堆叠小分子形成有序的空间排列，从而实现相邻分子之间的三维电荷转移。 SICTERS纳米探针的拉曼散射截面比相似粒径的传统SERS金纳米探针高1350倍。 SICTERS 在体内成像灵敏度、分辨率和深度方面优于 SERS。 SICTERS 能够对血液和淋巴管系统进行无创拉曼成像，这是 SERS 无法实现的。 SICTERS 代表了一种增强拉曼散射的替代技术，用于指导超灵敏无基底拉曼成像探针的设计。