Although nanotechnology has been investigated during recent years to increase the bioavailability and therapeutic effects of mucosal administrated drugs, numerous barriers (e.g., pH environment, enzymes and mucus) still limit the delivery efficiency. And the epithelium would also affect the systemic mucosal drug delivery. Amongst all the barriers, the protective mucus has drawn more and more attention, which strongly hinders the accessibility of nanovehicles to epithelium. Therefore, trials to conquer the mucus barrier have been designed using two controversial strategies: mucoadhesion and mucus-penetration. This review summarizes the influence of mucus layer on nanomaterials and introduces the modification strategies by modulating surface properties (i.e., hydrophilicity/hydrophobicity and surface charge) to overcome mucus barriers. Furthermore, it also reviews advanced modification methods to meet the different surface requirements of nanovehicles to overcome mucus and epithelium barriers in systemic mucosal delivery.