The Landscape of Ferritin Nanocages for Neurodegenerative Diseases Treatment

The blood-brain barrier (BBB) is a sophisticated structure composed of brain capillary endothelial cells, basement membrane, and neuroglial membrane, which strictly regulates substance exchange between the blood and brain tissue. While maintaining the homeostasis of the central nervous system, it blocks the entry of over 98% of small-molecule drugs and nearly all macromolecular drugs into the brain parenchyma, posing a significant challenge for the treatment of neurodegenerative diseases (NDs). Owing to their unique hollow architecture, favorable biocompatibility, reversible self-assembly properties, intrinsic targeting capability, and surface modifiability, natural ferritin nanocages have garnered substantial attention in the fields of biomedicine and nanotechnology. This review outlines the pathological mechanisms of NDs, the structure and function of the BBB, as well as its transport mechanisms. It highlights the advantages of ferritin nanocages in crossing the BBB-attributed to their natural nanostructure, brain-targeting potential, and capacity for functionalized surface modification-along with their drug loading capacity, antioxidant activity, and favorable biosafety profile. Recent advances in the application of natural ferritin nanocages for the diagnosis and therapy of NDs are also summarized. However, it is important to note that the evidence supporting their application in NDs remains more limited compared to their extensive research in cancer therapeutics. Finally, current challenges and future prospects of ferritin-based nanoplatforms are discussed, providing valuable insights for developing ferritin nanocage-based strategies in the diagnosis and treatment of NDs.