SIMPLE: Structured illumination based point localization estimator with enhanced precision.

We present a structured illumination microscopy based point localization estimator (SIMPLE) that achieves a 2-fold increase in single molecule localization precision compared to conventional centroid estimation methods. SIMPLE advances the recently introduced MINFLUX concept by using precisely phase-shifted sinusoidal wave patterns as nanometric rulers for simultaneous particle localization based on photon count variation over a 20 μm field of view. We validate SIMPLE in silico and experimentally on a TIRF-SIM setup using a digital micro-mirror device (DMD) as a spatial light modulator.