DESIGN AND DEVELOPMENT OF INNOVATIVE DRUG DELIVERY SYSTEMS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES WITH HIGH TERRITORIAL IMPACT

Sardinia’s genetic isolation has led to a high prevalence of autoimmune and neurodegenerative disorders, notably Multiple Sclerosis (MS). This doctoral research addresses MS as a regional priority, focusing on drug repurposing and advanced delivery systems. Specifically, the study investigates Clemastine Fumarate, a potent remyelinating agent limited by poor administration profiles. To overcome these barriers, Lemon-derived Extracellular Nanovesicles (LENVs) were developed as a sustainable delivery platform, aligning with circular economy principles by utilising regional botanical resources. The project was executed in four strategic phases: 1. Sustainable Extraction and Biological Evaluation: A solvent-free method was developed to isolate LENVs from lemon pulp. These were loaded with Clemastine and tested on an oligodendrocyte progenitor cell (OPC) model. Results indicate that Clemastine-loaded LENVs modulate intracellular calcium dynamics, a key mechanism for overcoming differentiation blocks and promoting remyelination. 2. Technological Optimisation: To ensure industrial scalability, a wet media milling technique was refined using Design of Experiments (DoE). This enabled the rapid production of uniform vesicles while maintaining optimal antioxidant properties and low cytotoxicity. 3. Waste Valorisation and Nasal Formulation: The extraction by-product was upcycled into a mucoadhesive gel for intranasal delivery. This route targets direct nose-to-brain transport, bypassing the blood-brain barrier to enhance therapeutic distribution in neural tissues. 4. Surface Modification: LENVs were engineered into a hybrid nanosystem by coating them with Hyaluronic Acid (HA). This modification targets CD44 receptors, which are upregulated in neuroinflammatory CNS pathologies. Furthermore, HA’s mucoadhesive nature increases residence time in the nasal cavity, facilitating efficient translocation of the encapsulated cargo.