When higher resolution reduces precision: quantum limits of off-axis interferometric scattering microscopy

Coherent interferometric scattering microscopy (i scat) enables nanoparticle tracking on microsecond timescales and with nanometer precision, and has become a key tool in structural and cellular biophysics. The achievable localization precision in such experiments is fundamentally limited by photon shot noise. Here, we analyze three-dimensional localization precision for spherical subwavelength scatterers in a homogeneous medium under oblique illumination in iscat using the framework of (Quantum) Fisher information. We show that tilting the illumination can enhance localization precision and accuracy per detected photon, while increasing robustness to defocusing. Surprisingly, rotating coherent scattering microscopy, which incoherently averages oblique illuminations, achieves higher spatial resolution but lower localization precision. Our results establish the quantum limits of off-axis interferometric imaging and reveal that resolution and precision can behave in opposite ways—a key insight for designing next-generation coherent microscopes.