Nanoparticles in Delivery Across the Blood-Brain Barrier

The blood-brain barrier (BBB) is a critical physiological structure that limits the delivery of therapeutic agents to the central nervous system (CNS), posing a major challenge in the treatment of neurological diseases. Lipid nanoparticles (LNPs) have emerged as effective drug carriers due to their high biocompatibility, efficient encapsulation, and ability to facilitate intracellular delivery. Current research has explored multiple strategies to transport LNPs across the BBB, including direct intracerebral injection, receptor-mediated transcytosis (RMT), adsorptive-mediated transcytosis (AMT), and transporter-mediated transcytosis (TMT). These methods have demonstrated varying degrees of success in preclinical studies, with improvements in targeting efficiency, tissue distribution, and gene expression. Despite these advances, a comprehensive comparative understanding of the strengths and limitations of each delivery route remains insufficient, particularly regarding clinical translation and safety. This review analyzes four major LNP-based delivery approaches across the BBB, focusing on their mechanisms, representative applications, and practical limitations. Direct injection offers precise delivery but is invasive and limited in distribution. RMT provides high specificity but is affected by receptor expression variability. AMT and TMT offer receptor-independent or nutrient-mimicking routes but may cause off-target effects or disrupt normal transport processes.