Skin diseases may cause rash, inflammation, itchiness, and other important skin changes, including dysplasia. Some skin conditions may be due to genetic and lifestyle factors and immune-mediated factors. The current skin disease treatment can include oral medication, topical cream, or ointments. Nanotechnology is revolutionizing the drug delivery systems, increasing the time life of active therapeutic compounds and improving the treatment efficiency. This work hypothesizes that varying the surface properties of chitosan nanoparticles (Ch-NPs) can modulate their diffusion through dermal tissue. Thus, Ch-NPs were synthesized, and their surface was modified with polyethylene glycol, oxalic acid, and linoleic acid for transdermal therapy. The different Ch-NPs were labeled with a fluorophore, and the dermal diffusion was measured on human skin by histological preparations and fluorescent microscopy. The surface properties of nanoparticles were shown to play an essential role in skin diffusion rate. Surface modification with a lipophilic moiety such as linoleic fatty acid showed a diffusion rate of 7.23 mm