BPS2026 – SICM as a novel tool: From single-protein detection to material properties of biomolecular condensates

Scanning ion conductance microscope (SICM) is a promising tool for biosensing owing to its unmatched spatial precision and applied force. We demonstrate the use of the platform in two contexts: (1) controlled sensing of user defined aptamer-based protein targets and (2) non-contact stiffness measurement of biomolecular condensate. First, we propose a strategy for disease biomarker detection in which protein targets are bound to programmable aptamer sequences attached to DNA carriers and identified via translocation through a solid-state nanopore. To overcome the limitations of free-translocation methods—i.e., low detection rates and poor signal-to-noise ratios—we introduce an SICM-based system capable of repeated sensing of the same molecule with controlled speed. Using this approach, we were able to detect molecules even in biological fluids. The carriers are engineered with multiple aptamer binding sites to enhance capture efficiency, achieving a detection rate of up to 74%, compared to just 14% with standard nanopore techniques. Precise spatial control allows for higher aptamer site density on each carrier, enabling user-defined programmability and broadening the system’s applicability to a wide range of disease biomarkers. Next, we applied SICM as a non-contact 3D imaging tool that allows for extraction of the material properties of the biomolecular condensates. We focus on Dhh1 proteins that are important for degradation of mRNA. In our study, we are investigating different protein structures of Dhh1—delta C, delta N, core domain, mCherry labelled, and its evolution through time. We demonstrate differences in material properties, highlighting the capabilities of the instrument. Our measurements are compared with established techniques such as optical tweezer-based fusion assays and fluorescence recovery after photobleaching (FRAP). Overall, these two applications demonstrate the versatility of SICM for biosensing in both applied and fundamental biological settings.