Small-Molecule Detection in Biological Fluids: The Emerging Role of Potentiometric Biosensors

Detecting small molecules in biological fluids is essential for diagnosing diseases, monitoring therapy, and studying how the body works. Traditional biosensing methods—such as amperometric, optical, or piezoelectric systems—offer excellent sensitivity but often rely on complex instruments, additional reagents, or time-consuming sample preparation. Potentiometric biosensors, by contrast, provide a simpler, low-power, and label-free alternative that can operate directly in biological environments. This review explores the latest progress in potentiometric biosensing for small-molecule detection, focusing on new solid-contact materials and advanced sensing membranes and compact device designs. We also discuss key challenges, including biofouling, matrix effects, and signal drift, together with promising strategies such as antifouling coatings, nanostructured interfaces, and calibration-free operation. Finally, we highlight how combining potentiometric sensors with artificial intelligence, digital data processing, and flexible electronics is shaping the future of personalized and point-of-care diagnostics. By summarizing recent advances and identifying remaining barriers, this review aims to show why potentiometric biosensors are becoming a powerful and versatile platform for next-generation biomedical analysis.