Yu-Shuan Chen, Hsin-Yi Huang
Alzheimer's disease (AD) remains a major global health challenge, as currently available therapies have a limited impact on disease progression and rely largely on systemic administration. Effective treatment is further hindered by the blood-brain barrier, which restricts brain exposure for most therapeutic agents. Intranasal delivery offers a noninvasive nose-to-brain approach by utilizing olfactory and trigeminal pathways to bypass systemic circulation and first-pass metabolism. Clinically, intranasal insulin and mesenchymal stromal cell-derived exosomes have demonstrated feasibility and safety in mild cognitive impairment and AD, and imaging studies have confirmed direct brain uptake following intranasal dosing. However, variable clinical outcomes suggest that therapeutic efficacy is determined primarily by formulation properties rather than by the delivery route alone. This review adopts a material-centric perspective to summarize rational intranasal formulation strategies for AD, including chitosan derivatives, thermoresponsive poloxamer and amphiphilic block copolymer platforms, lipid-based nanocarriers, surface-engineered systems, and biomimetic nanovesicles. Key translational considerations are discussed with emphasis on quantitative validation of brain exposure and reproducibility. Emerging methodological tools are briefly noted as potential facilitators of formulation development, without detracting from the central role of rational material design.