Nature Reviews Materials, Published online: 01 December 2025; doi:10.1038/s41578-025-00863-6Potentiometric immunoassays using field-effect transistors offer ultrasensitive protein detection for point-of-care and early diagnostics. This Perspective introduces a framework distinguishing a double-layer regime active at nanomolar antigen concentrations and a ΔpH-enabled regime active at sub-femtomolar concentrations, and examines the potential underlying mechanisms.