Conundrums of Localized Surface Plasmon Resonance Biosensors

ABSTRACT Localized surface plasmon resonance (LSPR) biosensing offers label‐free, real‐time detection of biomolecular interactions with high sensitivity and compact instrumentation. However, despite widespread use, several persistent and poorly understood phenomena limit the reproducibility, quantitation, and interpretability of LSPR signals. This perspective examines six recurring “conundrums” in LSPR biosensing, with a focus on their physical origins, experimental manifestations, and current approaches to mitigation. I review puzzling cases where analyte binding induces either red or blueshifts of the plasmon resonance; the difficulty of isolating the surface‐confined signal from bulk refractive‐index drift in microfluidics; the finite decay length of the plasmon field and the resulting saturation for thick or inhomogeneous layers; environmental cross‐sensitivities to temperature, pH, and ionic strength; run‐to‐run variability in nanostructure fabrication; and spectral congestion in multiplexed measurements. For each, I discuss the state of understanding, identify open questions, and outline strategies from advanced optical readouts to algorithmic baseline correction that could enable truly quantitative, drift‐immune, and reproducible LSPR biosensing.