Navigating Neurotoxicity and Safety Assessment of Nanocarriers for Brain Delivery: Evaluation Models and Insights.

Nanomedicine, an area which uses nanomaterials for theragnostic purposes, is advancing rapidly, particularly in the detection and treatment of neurodegenerative diseases. The design of nanocarriers can be optimized to enhance drug bioavailability and targeting to specific organs, improving therapeutic outcomes. However, clinical translation hinges on biocompatibility and safety. Nanocarriers can cross the blood-brain barrier (BBB), potentially causing neurotoxic effects through mechanisms such as oxidative stress, DNA damage, and neuroinflammation. Concerns about their accumulation and persistence in the brain make it imperative to carry out a nanotoxicological risk assessment. Generally, this involves identifying exposure sources and routes, characterizing physicochemical properties, and conducting cytotoxicity assays both in vitro and in vivo. The lack of a specialized regulatory framework creates substantial gaps, making it challenging to translate findings across development stages. Additionally, there is a pressing need for innovative testing methods due to constraints on animal use and the demand for high-throughput screening. This review examines the mechanisms of nanocarrier-induced neurotoxicity and the challenges in risk assessment, highlighting the impact of physicochemical properties and the advantages and limitations of current neurotoxicity evaluation models. Future perspectives are also discussed. Additional guidance is crucial to improve the safety of nanomaterials and reduce associated uncertainty. STATEMENT OF SIGNIFICANCE: Nanocarriers show tremendous potential for theragnostic purposes in neurological diseases, enhancing drug targeting to the brain, and improving biodistribution and pharmacokinetics. However, their neurotoxicity is still a major field to be explored, with only 5% of nanotechnology-related publications addressing this matter. This review focuses on the issue of neurotoxicity and safety assessment of nanocarriers for brain delivery. Neurotoxicity-relevant exposure sources, routes and molecular mechanisms, along with the impact of the physicochemical properties of nanomaterials, are comprehensively described. Moreover, the different experimental models used for neurotoxicity evaluation are explored at length, including their main advantages and limitations. To conclude, we discuss current challenges and future perspectives for a better understanding of risk assessment of nanocarriers for neurobiomedical applications.