Plasmon-Enhanced Nanosensing: From Single Proteins to Therapeutic Nanoparticles

Plasmonic nanosensing, in which plasmon-enhanced near fields are used for single-molecule detection andsingle-particlebiosensing,hasmovedbeyondensemblerefractive-indexmeasurements.Itnow interrogatesindividualproteins,transientmolecularcomplexes,photoexcitedredoxpartnersand heterogeneous therapeutic nanoparticles. Its defining advantage is not a universal detection limit. It is the ability to concentrate optical energy into nanometric volumes and to transduce properties that ensemble averagesconceal.Localizedsurfaceplasmonresonance,surface-enhancedRamanandinfrared spectroscopy, plasmon-enhanced fluorescence, nanoaperture optical trapping and hybrid optical–electrical nanopores each provide different observables: binding-induced spectral shifts, vibrational fingerprints, residence-time distributions, conformational fluctuations and particle-specific electrical signatures. This review synthesizes the electromagnetic, thermal and transport physics that govern these observables. It thenevaluatesrepresentativeapplications,fromsingle-proteindynamicsandweakprotein–protein interactionstowavelength-dependentcytochromec–cytochromecoxidasekinetics,single-virus detection, adeno-associated virus genome loading, extracellular vesicles and lipid nanoparticles. Unlike earlierreviewsorganizedbydeviceorbyenhancementmechanism,thisreviewtreatsplasmonic nanosensing as an inverse problem and a metrology problem. Particular attention is given to three issues: separatingmolecularheterogeneityfromspatiallyheterogeneousenhancement;separatinggenuine photochemistryfromphotothermalandresonance-detuningartifacts;andcorrectingclass-dependent capture before event counts are reported as sample composition.Closed-form illustrations show how capture bias and device-to-device variation can produce convincing but incorrect results. A minimuminformationreportingchecklistandamaturitymapareproposedsothatplasmonicsingle-entity measurementscanprogressfrom informativeresearchprobestotransferable,orthogonallyvalidated analytical methods.