BIOMIMETIC NANOPARTICLES MODULATE NEUROINFLAMMATION AND AMELIORATE COGNITIVE AND MOTOR DEFICITS IN A MOUSE MODEL OF SPORADIC ALZHEIMER’S DISEASE

Neuroinflammation and oxidative stress are closely intertwined processes that contribute to neuronal dysfunction and disease progression in neurodegenerative disorders, including Alzheimer’s disease (AD). Chronic inflammation accompanies synaptic impairment and cognitive decline, while their selective modulation remains poorly explored.
Here, we tested the efficacy of a modular proteo-lipidic vesicle platform (NPs) designed to mimic key CNS cell features and enable selective targeting of neuroinflammatory sites in a mouse model of sporadic AD induced by herpes simplex virus type-1 infection. In vitro characterization guided the selection of NP formulations, while in vivo evaluation informed the choice of intranasal administration over systemic delivery. Accordingly, when administered intranasally, biomimetic nanoparticles accumulated in brain regions and interacted with activated CNS cells, while showing reduced accumulation in peripheral organs. Across NP formulations generated under distinct activation and loading conditions, we observed a consistent attenuation of neuroinflammatory burden and oxidative stress–related responses in the AD brain. This effect extended across multiple brain regions and was accompanied by improved cognitive and motor performances, together with changes in AD-associated cellular features. These alterations were evident across molecular, histological and behavioral analyses, outlining a coherent pattern of neuroinflammation modulation and functional improvement. Together, these findings suggest NPs as a versatile approach to investigate and modulate neuroinflammation-driven dysfunction in AD, supporting their potential relevance for the development of targeted strategies in neurodegenerative disease contexts.
Grant support: "Finanziato dall’Unione europea –Next Generation EU– PNRR M6C2 - Investimento 2.1 Valorizzazione e potenziamento della ricerca biomedica del SSN”. PNRR-MAD-2022-12376667; CUP: C53C22001550006