Clozapine (CZP) is an atypical antipsychotic, the most effective for the treatment of resistant schizophrenia. With the aim of overcome the limitations of current dosage forms (tablets or suspensions) and routes of administration (oral and intramuscular), this research project proposes nanocarrier systems for intranasal (IN) administration of CZP. In particular, the systems have been developed for the direct nose-to-brain (N2B) route, which allows the direct delivery of the drug to the central nervous system (CNS), bypassing the blood-brain barrier (BBB). This study focusses on the development and investigation of two distinct types of lyophilized polymeric nanoparticles (NPs) consisting of poly- ɛ -caprolactone (PCL) or poly (lactic-co-glycolic acid) (PLGA). The lyophilized formulations were cryoprotected with 5 % (w/v) d-maltose for PLGA-NPs and 25 % (w/v) d-maltose for PCL-NPs. The NPs showed a size of approximately 200 nm, suitable for reuptake from the olfactory nerve to reach the brain directly after the IN administration. In vitro release studies performed in artificial cerebrospinal fluid (aCSF) and simulated nasal fluid (SNF) showed that PLGA NPs released 100 % of the drug in 4 days in SNF, while in aCSF they released about 80 % in 20 days. On the contrary, PCL-NPs released the entire amount of drug within 24 h in both fluids. Furthermore, preliminary in vitro mucoadhesion studies were performed on NPs in liquid form (suspensions) to compare the possible variation in their mucoadhesive properties with respect to powdered NPs, which were tested directly on pig nasal mucosa tissue, where permeability was also assessed. CZP-loaded NPs showed some interactions with mucin in vitro, but no ex-vivo mucoadhesiveness was demonstrated. Furthermore, the results of permeation indicated that the use of CZP-PCL-NPs did not increase the effective permeation of CZP into the mucosa; however, a faster onset of permeation compared to free CZP and a controlled profile were demonstrated. Toxicity studies on primary human olfactory mucosa cells extracted from volunteer patients and on MDCKII cells were also done. Finally, stability studies were carried out under different conditions: suspensions stored at 4 and 25 °C for 3 months, in SNF at 35 °C and in aCSF at 37 °C; dry powders were instead stored at 25 °C with 50 % relative humidity for 8 months. All the results demonstrated a greater stability of NPs in powder form and the absence of aggregation phenomena under artificial physiological conditions.