1 Surface-modified nanocarriers for nose-to-brain 2 delivery : from bioadhesion to targeting 3

In the field of nasal delivery, one of the most fascinating applications is the delivery of 20 drugs directly to the central nervous system bypassing the blood brain barrier. This approach would 21 provide a series of benefits, such as dose lowering and direct targeting of potent drugs, ultimately 22 reducing their systemic side effects. Recently, clinical trials have explored the nasal administration 23 of insulin for the treatment of Alzheimer’s disease, with promising results. The use of 24 nanomedicines could provide further options for making nose-to-brain delivery reality. In 25 particular, apart from the selection of devices able to deposit the formulation in the upper part of 26 the nose, surface modification of these nanomedicines appears the key strategy to optimize the 27 delivery of drugs from the nasal cavity to the brain. In this review, nanomedicines delivery 28 approaches based on surface electrostatic charges, mucoadhesive polymers, as well as chemical 29 moieties targeting nasal epithelium, will be discussed and critically evaluated for nose-to-brain 30 delivery. 31