Tackling neurodegeneration with by-product-based-nanohydrogels for the nose-to-brain-delivery of natural bioactive compounds

Neurodegenerative diseases, such as Alzheimer's disease, affecting millions of people worldwide, are mulfifactorial disorders characterised by the progressive loss of neurons in the central nervous system (CNS). Although each neurodegenerative disease exhibits specific pathological features, they also share some common molecular mechanisms, such as neuroinflammation and oxidative stress, and ageing is the primary risk factor for most of them. The lack of effective treatments and the complex nature of these diseases has developed a pressing need to identify multitarget-directed ligands to address the complementary pathways involved in these disorders. In this scenario, natural bioactive compounds (NBCs) constitute a unique source of privileged molecules with a safety profile and a vast multi-target potential. Among them, sulforaphane (SFN), an isothiocyanate derived from glucoraphariin present in Brassicaceae, and isoliquiritigeriin (ILQ), a flavonoid compound mainly found in the root of Glycyrrhiza Uralensis, have shown a great neuroprotective potential. Even though their in vivo application is limited due to SFN relative instability, and ILQ low bioavailability. On these bases, the aim of this project is to design an innovative biopolymer based on the conjugation between silkworm sericin by-product and hyaluronic acid, characterised by high biocompafibility and tailorable biodegradation rate. This innovative biomateiial will be exploited for the formulation of nanohydrogels (NG) loaded with SFN and ILQ to be administered by nasal route (nose-to-brain- delivery to bypassing blood brain barrier). External biocompatible and biodegradable ctoss-linkers will be considered to tailor both the rheological properties and the release behavior of the nanohydrogel. We expect that the novel nanohydrogel has the potential to promote the controlled release of the NBCs, increasing the CNS targeting. The neuroprotective activity of the designed nanohydrogels will be investigated both in vitro and in vivo models of neurodegeneration. Microglial BV-2 and neuron-like SH-SY5Y cell cultures will be used to investigate the anti- inflammatory and antioxidant activity of the new nanohydrogels while their anti-ageing activity will be studied in astrocytes. The most effective nanohyfiogel will be further studied in two mice models of neurodegeneration: proteolipid protein (PLP) induced experimental autoimmune encephalomyelitis (EAE) in SQL mice, and myelin oligodendrocyte glycoprotein (MOG)-induced EAE in C57B16 mice.