Intranasal hydrogels for Alzheimer's disease: from nasal-interface engineering to brain targeting and translational readiness

Intranasal hydrogels offer a strategy to address rapid mucociliary clearance, limited nasal residence, difficult payload properties, and insufficient brain exposure in Alzheimer's disease (AD). This Review evaluates hydrogel and hydrogel-associated systems across formulation architecture, nasal-interface performance, brain pharmacokinetics, pharmacodynamics, safety, and translation. Selected systems improved deposition or retention, controlled release, permeation, and central exposure relative to relevant comparators, with some also showing convergent behavioral and disease-relevant biological effects in preclinical models. The strongest evidence comes from matched comparisons that distinguish route effects from the incremental contributions of carriers and hydrogels. However, rheology, deposition, targeting metrics, statistical reporting, complete-product stability, repeated-dose safety, device performance, and human reproducibility remain inconsistently characterized. Overall, the evidence supports intranasal hydrogels as a credible preclinical platform for brain-directed AD drug delivery, but not as clinically validated therapy, and favors standardized, device-integrated, comparator-resolved development.