Entacapone is a catechol-O-methyltransferase (COMT) inhibitor, widely used for the symptomatic treatment of Parkinson's disease. However, it presents setbacks associated with a short half-life and a poor blood-brain barrier permeability. In order to surpass these limitations, entacapone was encapsulated in lipid-polymer hybrid nanoparticles (LPHNPs) functionalized with vitamin E (TPGS), using different liquid lipids as olive oil and coconut oil, and the co-surfactant and penetration enhancer Transcutol® HP. Depending on the system chosen, the nanoformulations presented differences in the hydrodynamic sizes (DDLS) after synthesis, and an increasing particle size in the following order: Transcutol® HP< olive oil < coconut oil. The nanoformulations presented interaction with mucins and serum proteins, which anticipates a good permeability for oral and intranasal administration. No cytotoxic effects were observed in human neuroblastoma (SH-SY5Y), human hepatocellular carcinoma (HepG2), or squamous cell carcinoma (RPMI 2650) cell lines for concentrations below 10 µM. Furthermore, olive oil and Transcutol® HP nanoformulations maintained the COMT inhibition effect in HepG2 cells and presented antioxidant and iron chelation properties in SH-SY5Y cells. An increase in entacapone permeability was observed for Transcutol® HP nanoformulations using in vitro RPMI cells. In vivo study using Caenorhabditis elegans as a model demonstrated survival percentages > 80% after acute exposure to the nanoformulations in concentrations up to 40 μM in both wild-type (N2) and parkinson's disease model (WLZ3) strain, and antioxidant activity for HTT@Ent (40 μM) formulation in wlz3 strain. Overall, this work shows that the encapsulation of entacapone could be an interesting alternative in solving the drug performance by improving its physicochemical properties and permeability.