Overcoming the Brain Barriers: From Immune Cells to Nanoparticles

Most drug delivery strategies perform suboptimally in the CNS due to the presence of three major brain barriers: the blood–brain barrier, the blood–leptomeningeal barrier, and the blood–cerebrospinal fluid barrier. Immune cells use a plethora of molecules to bypass the different barriers and infiltrate the CNS under homeostasis and in diverse pathological contexts. Nanoparticulate carriers, often shortened to nanoparticles (NPs), have recently emerged as superior vehicles capable of protecting drugs while also promoting tissue-specific delivery, but remain ineffective in transporting pharmaceutical agents into the CNS. Exploiting the molecular and cellular pathways used by immune cells to overcome the protective brain barriers may prove useful for enhancing NP delivery into the CNS. Nanoparticulate carriers, often referred to as nanoparticles (NPs), represent an important pharmacological advance for drug protection and tissue-specific drug delivery. Accessing the central nervous system (CNS), however, is a complex process regulated by mainly three brain barriers. While some leukocyte (i.e., immune cell) subsets are equipped with the adequate molecular machinery to infiltrate the CNS in physiological and/or pathological contexts, the successful delivery of NPs into the CNS remains hindered by the tightness of the brain barriers. Here, we present an overview of the three major brain barriers and the mechanisms allowing leukocytes to migrate across each of them. We subsequently review different immune-inspired and -mediated strategies to deliver NPs into the CNS. Finally, we discuss the prospect of exploiting leukocyte trafficking mechanisms for further progress. Nanoparticulate carriers, often referred to as nanoparticles (NPs), represent an important pharmacological advance for drug protection and tissue-specific drug delivery. Accessing the central nervous system (CNS), however, is a complex process regulated by mainly three brain barriers. While some leukocyte (i.e., immune cell) subsets are equipped with the adequate molecular machinery to infiltrate the CNS in physiological and/or pathological contexts, the successful delivery of NPs into the CNS remains hindered by the tightness of the brain barriers. Here, we present an overview of the three major brain barriers and the mechanisms allowing leukocytes to migrate across each of them. We subsequently review different immune-inspired and -mediated strategies to deliver NPs into the CNS. Finally, we discuss the prospect of exploiting leukocyte trafficking mechanisms for further progress. a glial population that supports the BBB and ensheathes it using cellular extensions known as astrocytic endfeet. Astrocytes carry out numerous other functions in the CNS as well. a highly vascularized structure lining the brain ventricles and producing CSF. colloidal dispersion is a heterogeneous system comprising particles dispersed in a continuous phase such as NPs in biological fluid. Colloidal stability refers to the ability of NPs to remain homogeneously dispersed without phenomena like aggregation and sedimentation taking place. movement of particles in a moving fluid; for example, the transport of NPs by circulating blood flow and CSF. relates to the movement of particles from a region of high concentration to one with low concentration. NP diffusion rates depend on their size, the medium’s viscosity, the diffusion space, and possible interactions with the surrounding environment. an animal model of autoimmune neuroinflammation generally used to study neuroinflammatory processes reminiscent of MS. time required for the NP plasma concentration to be reduced by half. Half-life is a measure of the speed of elimination. a collection of novel NP delivery approaches based on the trafficking mechanisms of immune cells or that directly employ immune cells for NP delivery (i.e. leukocyte-mediated NP delivery). white blood cells implicated in innate and adaptive immune responses and comprising multiple cell populations and subpopulations (e.g., neutrophils, monocytes, T and B lymphocytes, etc.). resistance to elastic (nonpermanent) deformation of a particle when a stress is applied to it. pharmaceutical structures in the 1–100-nm-diameter range used to transport and deliver therapeutic or imaging agents in pathological contexts or for diagnostics. a type of mural cells usually found embedded in EC basement membrane.