Intranasal Nano-Enabled Therapies for Alzheimer’s Disease: A Comprehensive Review of Nose-to-Brain Pathways, Smart Lipid–Polymer Hybrid Carriers, and Clinical Translation

Abstract

Alzheimer disease (AD) is now affecting over 55 million individuals across the globe, and it has a yearly cost that is as high as the gross domestic product of most of the middle-sized countries. Approved pharmacotherapies, mainly acetylcholinesterase (AChE) inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists, have short-lived symptomatic effects and achieve low brain exposure because >98% of small molecules fail to cross the blood–brain barrier (BBB).The intranasal route of nose-to-brain (N2B) delivery is also used to circumvent the BBB by olfactory and trigeminal pathways to provide a rapid exposure of central nervous system (CNS) with negligible systemic toxicity. Nonetheless, mucociliary clearance, epithelial atrophy (age-related) and the absence of standardized formulationcharacterization frameworks have impeded the process of translation. In this review, recent advances in the field of smart nano-composite carriers, particularly, mucoadhesive, thermoresponsive lipid-polymer hybrids hydrogels, in AD treatment, are summarized. The emphasis is on design rationale, critical quality attributes, in-vivo performance and regulation with consideration to dual-cargo strategies, which are symptomatic and disease-modifying agents’ combinations.In parallel, the regulatory landscape has shifted: lecanemab (Leqembi) gained EU authorisation in April 2025 and donanemab (Kisunla) received US FDA approval in July 2024 with a positive CHMP opinion in July 2025, underscoring the therapeutic momentum in AD monoclonal antibodies even as delivery challenges remain.