Intranasal drug delivery for neurodegenerative diseases: therapeutic opportunities across molecules, organelles, and cells

Abstract

Neurodegenerative diseases (NDDs) are a heterogeneous group of disorders characterized by progressive neuronal loss that leads to cognitive, motor, and behavioral impairment. With population aging, NDDs impose an expanding medical and socioeconomic burden, yet most available treatments remain symptomatic rather than disease modifying. Disease mechanisms are increasingly understood as multicellular processes involving neurons, astrocytes, microglia, and other cell types, which complicates target selection and limits translation from conventional models. Intranasal administration offers a noninvasive route for delivering therapeutics to the central nervous system by leveraging olfactory and trigeminal pathways and reducing dependence on blood-brain barrier penetration. This review summarizes recent advances in intranasal strategies for NDDs across diverse therapeutic classes, including peptides and proteins, small molecules and metabolic modulators, nucleic acid-based cargos, and nanocarrier enabled formulations designed to improve retention, stability, and brain deposition. We further highlight emerging organelle centered and bioengineered approaches, such as mitochondrial delivery and other cell organelle or organelle derived systems, alongside cell-based and cell-free biologics including stem cells, secretomes, and extracellular vesicles that provide multi target neuroprotective and immunomodulatory effects. Finally, we discuss key translational challenges, including limited delivery efficiency due to mucociliary clearance, uncertainty in dosing regimens, manufacturing and quality control for complex biologics and organelles, and the need for robust biomarkers and imaging readouts to confirm central target engagement. Collectively, these advances position intranasal delivery as a versatile but evolving platform for next generation interventions in NDDs.