Precision Nanocrystal Theranostics for Neurodegenerative Proteopathies: Strategies to Cross the Blood-Brain Barrier and Target Protein Aggregation

This review examines nanocrystal-based theranostic platforms as a promising method to overcome the blood-brain barrier (BBB) in neurodegenerative diseases like Alzheimer’s and Parkinson’s. These neurological diseases involve gradual protein misfolding and aggregation, causing neuronal damage and loss. Although molecular diagnostics and treatments have advanced, the BBB remains a major challenge, preventing most diagnostic and therapeutic agents from reaching the central nervous system. By integrating dense diagnostic nanocrystal cores with stimuli-responsive biodegradable polymers, these systems facilitate targeted detection and localized therapy within the brain. The review evaluates recent BBB-crossing techniques, such as receptor-mediated transcytosis and surface modifications like "stealth" coatings to evade efflux transporters. Nanocrystals serve a dual role: as highly sensitive imaging agents for early detection of amyloid-β, tau, and other protein aggregates, and as delivery vehicles for gene-silencing agents, small-molecule inhibitors, and therapeutics that reduce proteotoxicity. It also discusses challenges for clinical use, including safety concerns like neurotoxicity, long-term biodegradability, off-target accumulation, and protein corona formation, along with strategies to improve safety, reproducibility, and scalability. Overall, nanocrystal-based theranostics hold promise as an integrated platform for early diagnosis, targeted intervention, and ongoing monitoring of neurodegenerative proteopathies.