# Conundrums of Localized Surface Plasmon Resonance Biosensors

## TL;DR

This paper discusses challenges in LSPR biosensors, such as signal variability and environmental effects, and suggests ways to improve their accuracy and reliability.

## Contribution

The paper identifies and analyzes six key unresolved issues in LSPR biosensing and proposes mitigation strategies.

## Key findings

- LSPR signals can shift unpredictably due to analyte binding, complicating interpretation.
- Environmental factors like temperature and pH affect sensor readings, reducing reproducibility.
- Variability in nanostructure fabrication leads to inconsistent sensor performance.

## 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.

Localized surface plasmon resonance (LSPR) biosensing faces fundamental conundrums arising from finite field decay lengths, environmental cross‐sensitivities, and batch variability. Competing surface, bulk, and electrostatic effects can induce red or blue spectral shifts, complicating quantification, reproducibility, and interpretation in complex or multiplexed sensing environments. Created in BioRender. Bhalla, N. (2026) https://BioRender.com/p99uder.