Background <p>Hypoxic-ischemic encephalopathy (HIE) remains a major cause of neonatal mortality and long-term neurodevelopmental disability. Intranasally delivered mesenchymal stem cells and neurotrophic factors from breast milk have been detected in the central nervous system and may have a role in neuroregenerative processes. F-NEO-BRIGHT (Feasibility- NEOnatal- intranasal BReast milk, Impact on brain Growth in HIE Therapy) is the first clinical study aimed to assess the feasibility and safety of intranasal fresh breast milk (iFBM) in neonates with HIE in both inpatient and home settings.</p> Methods <p>This prospective, single-center study involved ten patients diagnosed with moderate to severe HIE treated with therapeutic hypothermia. Own-mother’s fresh breast milk expressed within 4 h, was given intranasally twice daily, 0.4 ml in each nostril, initiated within 48 h of life and continued until day 28.</p> Results <p>Under continuous cardiorespiratory and neurointensive monitoring in neonatal intensive care, the therapy was well tolerated with no adverse events or side effects observed. The intervention proved to be feasible, treatment initiation was achieved within 48 h in all enrolled neonates and was successfully continued by parents in the home setting.</p> Conclusion <p>iFBM in neonates with moderate to severe HIE is safe and feasible in both inpatient and home settings.</p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>F-NEO -BRIGHT Study is the first clinical trial where intranasal fresh breast milk is administered to neonates with neonatal encephalopathy.</p> </ItemContent> <ItemContent> <p>Intranasal fresh breast milk administration during the first month of life appears to be feasible, safe and well-tolerated both in hospital and in the home settings.</p> </ItemContent> <ItemContent> <p>The full therapeutic potential of this treatment could be revealed by further research into long-term neurodevelopmental outcomes.</p> </ItemContent> </UnorderedList></p>