Precision drug delivery to the central nervous system using engineered nanoparticles

Development of novel therapies for central nervous system (CNS) disorders has experienced a high failure rate in clinical trials owing to unsatisfactory efficacy and adverse effects. One of the major reasons for limited therapeutic efficacy is the poor penetration of drugs across the blood–brain barrier. Despite the development of multiple drug delivery platforms, the overall drug accumulation in the brain remains sub-optimal. Another critical but overlooked factor is achieving precision delivery to a specific region and cell type in the brain. This specificity is crucial because most neurological disorders exhibit region-specific vulnerabilities. Multiple trials have failed owing to adverse CNS effects induced by nonspecific drug targeting. In this Review, we highlight the key regions and cell types that should be targeted in different CNS diseases. We discuss how physiological barriers and disease-mediated changes in the blood–brain barrier and the overall brain can impact the precision delivery of therapeutics via the systemic route. We then perform a systematic analysis of the current state-of-the-art approaches developed to overcome these barriers and achieve precision targeting at different levels. Finally, we discuss potential approaches to accelerate the development of precision delivery systems and outline the challenges and future research directions. The development of therapeutics for central nervous system disorders suffers from high failure rates owing to poor blood–brain barrier penetration and lack of targeted delivery. This Review discusses how nanoparticles can help to overcome these challenges to enable precision targeting of the brain for different central nervous system diseases.