involving the bscb aims to find efficient methods of overcoming its barrier mechanism to improve drug delivery. this can include directly bypassing the barrier, such as by placing a drug-eluting depot or injecting directly into the cns, preventing efflux, such as with p-glycoprotein inhibitors, or by enhancing drug penetration. disruption the bbb/bscb can be deliberately disrupted to increase paracellular transport of drugs to the cns. an established method of accomplishing this is through osmotic disruption. csf is nearly isosmotic to blood, so if a hyperosmotic agent, such as mannitol, is administered intravascularly, the osmolarity gap between the blood and csf widens, resulting in fluid flow from cns tissue into blood vessels. hyperosmotic agents are already in clinical use as diuretics, though mannitol is also approved to treat increased intracranial pressure, as it draws fluid out of the brain and thus decreases the volume-induced pressure. however, hyperosmolarity may also be of use in drug delivery since it causes the membranes of endothelial cells to shrink, resulting in tight junctions stretching and paracellular gaps widening. widened paracellular gaps can facilitate passage of larger molecules that otherwise would be unable to cross the bbb/bscb. this method is not commonly used due to adverse effects such as dehydration and, in some cases, exacerbation of injury. nanoparticles nanoparticles are composed of nano-sized particles that have widespread medical application. there are different types of nanoparticle, including polymeric (natural and artificial), liposomal/lipid-based, and inorganic. the most relevant nanoparticle type to treating cns disease are lipid-based nanoparticles, as the lipophilicity of the particle allows for higher permeability in the bbb/bscb. the goal of nanoparticles in this context are to successfully enter cns tissue and release its drug cargo safely. they gain entry in two major ways: adsorption-mediated transport and receptor-mediated transport. in adsorption-mediated transport, the nanoparticle is covered in positive charges that interact with the negative charges found on the endothelium. in receptor-mediated transport, nanoparticles are covered in ligands that bind receptors found on the bbb/bscb, so that when it encounters these receptors, endocytosis is triggered, and the nanoparticle is ferried across the endothelium. there is ongoing issue with nanoparticles as a whole, particularly regarding accumulation in the targeted region and cytotoxicity; 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