Nanoparticles are known to form in narrow slip zones in natural and experimental fault zones, but their possible role in dynamic weakening of faults during seismic slip remains almost unexplored. We conducted friction experiments on periclase (MgO) nanoparticles (50 nm in average size) at rates as high as 1.3 m s−1, a typical speed of seismic slip. The nanoparticles were used as the initial gouge to avoid complexities arising from comminution and fluid release. The dynamic friction decreased with increasing slip rate and the steady-state frictional coefficient reduced to as low as 0.1 at a slip rate of 1.3 m s−1. Flash heating is not effective for nanoparticles, and we propose that development of slickensides and dominant operation of nanoparticle rolling cause such a weakening. Nanoparticle lubrication appears to be as effective as melt lubrication and thermal pressurization, and the formation of nanoparticles in slip zones may be an important fault lubrication process.