Oriented nanobody–field-effect transistor interfaces enable ultrasensitive cancer biomarker detection

Sensitive, reliable detection of molecular biomarkers in complex clinical samples through portable biosensors remains a central challenge for early cancer diagnostics. Field-effect transistor (FET) biosensors offer strong potential for miniaturized, low power sensing, yet their clinical translation is often constrained by probe instability, non-specific adsorption and Debye screening-limited signal transduction in serum. Here we present a site-specific anchored FET platform (SNAP-FET) that integrates genetic code expansion and click chemistry to immobilize nanobodies with a controlled, uniform, site-specific orientation in serum, within the Debye length for efficient signal transduction. This strategy yields attomolar-level sensitivity and stable electronic readout of endometrial cancer biomarkers directly in serum, overcoming longstanding limitations of biofluid FET sensing by coupling compact affinity probes with precision interface design. More broadly, the SNAP-FET and its portable implementation, ENDOCARE, provide a generalizable framework for next-generation biochemical sensing in point-of-care settings for early diagnostics in oncology.