Abstract: Brain-penetrating polymeric nanoparticles that can be loaded with drugs and are optimized for intracranial convection-enhanced delivery (CED) have been developed. In the preferred embodiment, these are loaded with FDA-approved compounds, identified through library screening to target brain cancer stem cells (BSCSs). The particles are formed by emulsifying a polymer-drug solution, then removing solvent and centrifuging at a first force to remove the larger particles, then collecting the smaller particles using a second higher force to sediment the smaller particles having a diameter of less than 100 nm, more preferably less than 90 nanometers average diameter, able to penetrate brain interstitial spaces.