Intranasal delivery of Odorranalectin-modified lipid nanoparticles for multi-targeted therapy of Alzheimer's disease

Oxidative stress, neuroinflammation, and β-amyloid (Aβ) deposition act synergistically to drive Alzheimer’s disease (AD) progression. Effective treatment, therefore, requires multi-targeted strategies capable of addressing these interconnected pathological mechanisms. Here, an Odorranalectin (OL)-conjugated lipid nanoparticle (siB/QU@L-OL) was engineered for efficient intranasal delivery of β-site APP cleaving enzyme 1 (BACE1) siRNA (siB) and quercetin (QU). siB/QU@L-OL prepared via microfluidics exhibited uniform size distribution, high encapsulation efficiency, and robust stability. Following intranasal administration, OL surface modification enabled binding to L-fucose residues expressed on the olfactory epithelium, reducing mucociliary clearance and facilitating brain transport. In vitro , siB silenced BACE1 expression and inhibited Aβ generation, while QU alleviated Aβ-induced oxidative stress and neuroinflammation, thereby suppressing neuronal apoptosis. In APP/PS1 mice, siB/QU@L-OL restored Aβ homeostasis and redox balance, attenuated neuroinflammation and neuronal loss, and consequently improved cognitive performance. Collectively, this brain-targeted nanoplatform demonstrates strong potential for synergistic intervention in AD. • siB/QU@L-OL enables efficient nose-to-brain delivery. • siB/QU@L-OL silences BACE1 to reduce Aβ production. • siB/QU@L-OL activates PI3K/Akt/Nrf2 signaling to alleviate oxidative stress and neuroinflammation. • siB/QU@L-OL improves cognitive performance in AD mice.