We present a four-wave mixing interferometry technique recently developed by us, whereby single non-fluorescing gold nanoparticles are imaged background-free even inside highly heterogeneous cellular environments, owing to their specific nonlinear plasmonic response. The set-up enables correlative four-wave mixing/confocal fluorescence imaging, opening the prospect to study the fate of nanoparticle-biomolecule-fluorophore conjugates and their integrity inside cells. Beyond imaging, the technique features the possibility to track single particles with nanometric position localization precision in 3D from rapid single-point measurements at 1 ms acquisition time, by exploiting the optical vortex field pattern in the focal plane of a high numerical aperture objective lens. These measurements are also uniquely sensitive to the particle in-plane asymmetry and orientation. The localization precision in plane is found to be consistent with the photon shot-noise, while axially it is limited to about 3nm by the nano-positioning sample stage, with an estimated photon shot-noise limit of below 1 nm. As a proof-of- principle, the axial localization is exploited to track single gold nanoparticles of 25nm radius while diffusing across aqueous pockets in a dense agarose gel, mimicking a relevant biological environment.
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