Nanobody Receptors Enable High-Sensitivity Monitoring of IL-6 Using Molecular Pendulum Bioanalysis

The development of biomolecular sensing technologies with high sensitivity and specificity remains an important goal in modern analytical science. Molecular pendulum sensing has emerged as a new reagentless method capable of detecting a wide array of biomolecules directly in biological fluids. This sensing approach relies heavily on the modulation of hydrodynamic drag of molecular probes through solution, such that alterations in hydrodynamic diameter can transduce biomolecular interactions. Here, we explore the use of nanobodies as an alternative receptor in pendulum-based systems due to their small size and robust affinities. We compare the performance of nanobodies with that of aptamers and antibodies integrated into the molecular pendulum system by targeting the inflammatory indicator interleukin-6 (IL-6). Nanobody molecular pendulums demonstrate enhanced sensor response and sensitivity compared to those of the other receptors, enabling fine control over detection in the low physiological range of IL-6. In addition, we demonstrate the ability of nanobody sensors to function in complex biological matrices and at physiological temperature.