Harnessing intranasal delivery of natural plant extracts and tyramine-modified hyaluronan hydrogels for neuroprotection in neurodegenerative diseases

Neurodegenerative disorders are characterized by oxidative stress and neuroinflammation, calling for innovative therapeutic approaches with effective brain recovery. In this study, hyaluronic acid-tyramine (HA-Tyr) was synthesized via horseradish peroxidase/hydrogen peroxide crosslinking and characterized as intranasal carrier of Rosmarinus officinalis and Mentha rotundifolia extracts. Physicochemical analyses confirmed rheological stability, injectability, and mucoadhesive capacity, together with swelling profiles suitable for nasal mucosa. The functionalization with natural extracts provided strong antioxidant activity, while water-holding capacity remained within physiologically acceptable limits. Both extracts were efficiently encapsulated and exhibited a biphasic release profile over 24 h, highlighting the influence of phytochemical composition on release behaviour. Among the extracts, HA-Tyr/Rosmarinus officinalis significantly protected immortalized human neuroblastoma cells from neurotoxin-induced toxicity in a concentration-dependent manner, reducing reactive oxygen species and nitrite production. Downregulating Transient Receptor Potential Vanilloid 1 and Caspase-1 while enhancing β-Nerve Growth Factor expression, the formulations showed a promising potential in supporting neuronal survival. In vivo validation in a Parkinsonian mouse model revealed that intranasal administration of HA-Tyr/Rosmarinus officinalis restored motor coordination, forelimb use, and exploratory behaviour, while reducing anxiety-like responses. Importantly, these functional improvements occurred in the absence of dopamine restoration, although a restored dopamine metabolism, with reduced catabolic degradation (modulatory effect on 3,4-dihydroxyphenylacetic acid, DOPAC, production) was detected. In conclusion, neuroprotective and symptomatic effects were observed after HA-Tyr/Rosmarinus officinalis administration, supporting HA-Tyr hydrogels as promising mucoadhesive platform for intranasal delivery of neuroprotective compounds and bridging material innovation with translational potential.