The development of multi-functional nanoparticles is important in overcoming the poor stability and low mucus permeation of traditional drug delivery systems. Hence, the encapsulation of a model drug, resveratrol (RES), into zein-polydopamine-lecithin (ZPLs) nanoparticles was investigated through a delicately controlled phase separation process. The surface of the nanoparticles obtained was successfully modified with lecithin, which endowed them with neutral and hydrophilic properties. Due to the strong charge repulsion of the particles, the fabricated ZPLs showed high stability under the conditions of a saline solution, various pH, long-term storage and high-speed centrifugation. In vitro study suggested that the RES exhibited remarkably sustained release performance after loading into ZPLs. The quantificational experiment of the Transwell system suggested that most of the ZPLs could pass through mucus and exhibited high mucus permeation. This study provides a new opportunity to prepare RES-ZPLs nanospheres as a smart drug nanocarrier, with enhanced stability and mucus permeation.