The aim of this study was to prepare mucopenetrating nanoparticles with melatonin, as a novel drug delivery system for local application in the oral cavity with the aim to treat diseases of paradont. Nanoparticles were prepared by simple desolvation process, after the PEGilation with PEG in molecular mass ranging from 4 to 10 kDa. This assured sterical stabilisation of the nanoparticles as well as the mucopenetrative properties. The mean spherical diameter of the nanoparticles was around 200 nm, which is in the range suitable for mucopenetration. The obtained particles were monodisperse. Zeta potential in all cases was around -40 mV, therefore nanoparticle inetarction with the mucin chains and their aggregation should not be expected. The optimal characteristics were obtained in case of nanoparticles PEGylated with PEG 6000 during 60 min. Melatonin was sucessfully encapsulated in such nanoparticles. The melatatonin loaded nanoparticles in the solid state were prepared by freeze-drying using sucrose at concentration of 5% as cryo/lioprotectant. Althrough the encapsulation efficiency of melatonin into PEHylated polyanhidride nanoparticles was relativley low, its conntent is sufficient to obtain positive therapeutical effect in local treatment of peridontal diseases.