Mucus is a viscoelastic gel layer that typically protects exposed surfaces of the gastrointestinal (GI) tract, lung airways, and other mucosal tissues.Particles targeted to these tissues can be efficiently trapped and removed by mucus, thereby limiting the effectiveness of such drug delivery systems.In this study, we experimentally and theoretically demonstrated that cylindrical nanoparticles (NPs), such as mesoporous silica nanorods and calcium phosphate nanorods, have superior transport and trafficking capability in mucus compared with spheres of the same chemistry.The higher diffusivity of nanorods leads to deeper mucus penetration and a longer retention time in the GI tract than that of their spherical counterparts.Molecular simulations and stimulated emission of depletion (STED) microscopy revealed that this anomalous phenomenon can be attributed to the rotational dynamics of the NPs facilitated by the mucin fibers and the shear flow.These findings shed new light on the shape design of NPbased drug delivery systems targeted to mucosal and tumor sites that possess a fibrous structure/porous medium.