Three-dimensional (3D) surface-enhanced Raman scattering (SERS) substrates have demonstrated remarkable abilities of ultrasensitive and reproducible molecular detection. The combination of both electromagnetic and chemical enhancement processes, light trapping, and multiple scattering effects of 3D structures are what enhance their performance. The principles of underlying enhancements are summarized systematically, and the main types of 3D substrates—vertically aligned nanowires, dendritic and fractal nanostructures, porous frameworks and aerogels, core–shell and hollow nanospheres, and hierarchical hybrid structures—are categorized in this review. Advances in fabrication techniques, such as template-assisted growth, electrochemical and galvanic deposition, dealloying and freeze-drying, self-assembly, and hybrid integration, are critically evaluated in terms of structural tunability and scalability. Novel developments in the field of biosensing are also highlighted, including non-enzymatic glucose sensing, tumor biomarker sensing, and drug delivery. The remaining limitations, such as low reproducibility, mechanical stability, and substrate standardization, are also noted, and future directions, such as stimuli-responsive designs, multifunctional hybrid platforms, and data-driven optimization strategies of SERS technologies, are also included.

In this study, a MOF-199/Ag@Au SERS sensing structure was successfully synthesized by combining metal–organic frameworks (MOFs) with surface-enhanced Raman scattering (SERS) technology for the efficient detection of dopamine (DA), a biomarker for neurological diseases, in serum. Using electrochemical methods, a copper-based MOF (MOF-199) was synthesized in situ on copper substrates and further deposited with silver nanoparticles (AgNPs). Subsequently, gold nanoshells were encapsulated around these silver cores by in situ chemical deposition. This preparation process is simple, controllable, and inexpensive. Furthermore, a novel Azo reaction-based DA SERS method was proposed to detect 1 pM DA, which represents an improvement in sensitivity by two orders of magnitude compared to previous unlabeled SERS detection methods and by four orders of magnitude compared to another SERS approach proposed in this work. There was an excellent linear relationship (R² = 0.976) between the SERS signal at 1140 cm⁻¹ and the DA concentration (0.001 M~1 pM). The results indicate that the MOF-199/Ag@Au sensor structure can successfully achieve both the qualitative and quantitative detection of DA in serum, thus providing a robust technical basis for the application of SERS technology in the field of clinical neurological disease screening.