luminal surface of endothelial cells of the bbb. ligands coated on the nanoparticle's surface bind to specific receptors to cause a conformational change. once bound to these receptors, transcytosis can commence, and this involves the formation of vesicles from the plasma membrane pinching off the nanoparticle system after internalization. additional receptors identified for receptor-mediated endocytosis of nanoparticle delivery systems are the scavenger receptor class b type i (sr-bi), ldl receptor (lrp1), transferrin receptor, and insulin receptor. as long as a receptor exists on the endothelial surface of the bbb, any ligand can be attached to the nanoparticle's surface to functionalize it so that it can bind and undergo endocytosis. another mechanism is adsorption mediated transcytosis, where electrostatic interactions are involved in mediating nanoparticle crossing of the bbb. cationic nanoparticles (including cationic liposomes) are of interest for this mechanism, because their positive charges assist binding on the brain's endothelial cells. using tat-peptides, a cell-penetrating peptide, to functionalize the surface of cationic nanoparticles can further improve drug transport into the brain. magnetic and magnetoelectric nanoparticles in contrast to the above mechanisms, a delivery with magnetic fields doesn't strongly depend on the biochemistry of the brain. in this case, nanoparticles are literally pulled across the bbb via application of a magnetic field gradient. the nanoparticles can be pulled in as well as removed from the brain merely by controlling the direction of the gradient. for the approach to work, the nanoparticles must have a non-zero magnetic moment and have a diameter of less than 50 nm. both magnetic and magnetoelectric nanoparticles (mens) satisfy the requirements. however, it is only the mens which display a non-zero magnetoelectric (me) effect. due to the me effect, mens can provide a direct access to local intrinsic electric fields at the nanoscale to enable a two-way communication with the neural network at the single-neuron level. mens, proposed by the research group of professor sakhrat khizroev at florida international university (fiu), have been used for targeted drug delivery and externally controlled release across the bbb to treat hiv and brain tumors, as well as to wirelessly stimulate neurons deep in the brain for treatment of neurodegenerative diseases such as parkinson's disease and others. focused ultrasound studies have shown that focused ultrasound bursts can noninvasively be used to disrupt tight junctions in desired locations of bbb, allowing for the increased passage of particles at that location. this disruption can last up to four hours after burst administration. focused ultrasound works by generating oscillating microbubbles, which physically interact with the cells of the bbb by oscillating at a frequency which can be tuned by the ultrasound burst. this physical interaction is believed to cause cavitation and ultimately the disintegration of the tight junction complexes which may explain why this effect lasts for several hours. however, the energy applied from ultrasound can result in tissue damage. fortunately, studies have demonstrated that this risk can be reduced if preformed microbubbles are first injected before focused ultrasound is applied, reducing the energy required from the ultrasound. this technique has applications in the treatment of various diseases. for example, one study has shown that using focused ultrasound with oscillating bubbles loaded with a chemotherapeutic drug, carmustine, facilitates the safe treatment of glioblastoma in an animal model. this drug, like many others, normally requires large dosages to reach the target brain tissue diffusion from the blood, leading to systemic toxicity and the possibilities of multiple harmful side effects manifesting throughout the body. however, focused ultrasound has the potential to increase the safety and efficacy of drug delivery to the brain. toxicity a study was performed to assess the toxicity effects of doxorubicin-loaded polymeric nanoparticle systems. it was found that doses up to 400 mg/kg of pbca nanoparticles alone did not cause any toxic effects on the organism. these low toxicity effects can most likely be attributed to the controlled release and modified biodistribution of the drug due to the traits of the nanoparticle delivery system. toxicity is a highly important factor and limit of drug delivery studies, and a major area of interest in research on nanoparticle delivery to the brain. metal nanoparticles are associated with risks of neurotoxicity and cytotoxicity. these heavy metals generate reactive oxygen species, which causes oxidative stress and damages the cells' mitochondria and endoplasmic reticulum. this leads to further issues in cellular toxicity, such as damage to dna and disruption of cellular pathways. silver nanoparticles in particular have a higher degree of toxicity compared to other metal nanoparticles such as gold or iron. silver nanoparticles can circulate through the body and accumulate easily in multiple organs, as discovered in a study on the silver nanoparticle distribution in rats. traces of silver accumulated in the rats' lungs, spleen, kidney, liver, and brain after the nanoparticles were injected subcutaneously. in addition, silver nanoparticles generate more reactive oxygen species compared to other metals, which leads to an overall larger issue of toxicity. research in the early 21st century, extensive research is occurring in the field of nanoparticle drug delivery systems to the brain. one of the common diseases being studied in neuroscience is alzheimer's disease. many studies have been done to show how nanoparticles can be used as a platform to deliver therapeutic drugs to these patients with the disease. a few alzheimer's drugs that have been studied especially are rivastigmine, tacrine, quinoline, piperine, and curcumin. pbca, chitosan, and plga nanoparticles were used as delivery systems for these drugs. overall, the results from each drug injection with these nanoparticles showed remarkable improvements in the effects of the drug relative to non-nanoparticle delivery systems. this possibly suggests that nanoparticles could provide a promising solution to how these drugs could cross the bbb. one factor that still must be considered and accounted for is nanoparticle accumulation in the body. with long-term and frequent injections that are often required to treat chronic diseases such as alzheimer's disease, polymeric nanoparticles could potentially build up in the body, causing undesirable effects. this area for concern would have to be further assessed to analyze these possible effects and to improve them.