Unlocking the Gates: Therapeutic Agents for Noninvasive Drug Delivery Across the Blood-Brain Barrier

The blood-brain barrier (BBB) is a highly selective network of various cell types that acts as a filter between the blood and the brain parenchyma. Because of this, the BBB remains a major obstacle for drug delivery to the central nervous system (CNS). In recent years, there has been a focus on developing various modifiable platforms, such as monoclonal antibodies (mAbs), nanobodies (Nbs), peptides, and nanoparticles, as both therapeutic agents and carriers for targeted drug delivery to treat brain cancers and diseases. Methods for bypassing the BBB can be invasive or noninvasive. Invasive techniques, such as transient disruption of the BBB using low pulse electrical fields and intracerebroventricular infusion, lack specificity and have numerous safety concerns. In this review, we will focus on noninvasive transport mechanisms that offer high levels of biocompatibility, personalization, specificity and are regarded as generally safer than their invasive counterparts. Modifiable platforms can be designed to noninvasively traverse the BBB through one or more of the following pathways: passive diffusion through a physio-pathologically disrupted BBB, adsorptive-mediated transcytosis, receptor-mediated transcytosis, shuttle-mediated transcytosis, and somatic gene transfer. Through understanding the noninvasive pathways, new applications, including Chimeric Antigen Receptors T-cell (CAR-T) therapy, and approaches for drug delivery across the BBB are emerging.