In this study, clobetasol propionate-loaded lecithin/chitosan nanoparticles in chitosan gel demonstrated a significantly higher anti-inflammatory activity compared to a sodium deoxycholate gel and commercial cream (Dermovate) containing the same drug. This result was obtained despite the 10-fold lower (0.005% vs. 0.05%) drug concentration in the nanoparticle-enabled formulation. This result can be explained by considering the well-known capability of nanoparticles to accumulate inside the hair follicles, thus forming a reservoir that slowly releases the drug. In this latter case, the biodegradability of the nanoparticles could be the basis of a further capability of these nanocarriers to promote absorption through the skin. In fact, as a consequence of their specific composition, i.e., polysaccharides and lipids, lecithin/chitosan nanoparticles are most likely biodegraded by enzymes present in skin secretions, such as lysozyme.