Abstract
The blood-brain barrier (BBB) selectively restricts the entry of molecules from peripheral circulation into the central nervous system (CNS) parenchyma. Despite this protective barrier, bacteria and other pathogens can still invade the CNS, often as a consequence of immune deficiencies or complications following neurosurgical procedures. These infections are difficult to treat since many bacteria, such as Staphylococcus aureus, encode a repertoire of virulence factors, can acquire antibiotic resistance, and form biofilm. Additionally, pathogens can leverage virulence factor production to polarize host immune cells towards an anti-inflammatory phenotype, leading to chronic infection. The difficulty of pathogen clearance is magnified by the fact that antibiotics and other treatments cannot easily penetrate the BBB, which requires extended regimens to achieve therapeutic concentrations. Nanoparticle systems are rapidly emerging as a promising platform to treat a range of CNS disorders. Nanoparticles have several advantages, as they can be engineered to cross the BBB with specific functionality to increase cellular and molecular targeting, have controlled release of therapeutic agents, and superior bioavailability and circulation compared to traditional therapies. Within the CNS environment, therapeutic actions are not limited to directly targeting the pathogen, but can also be tailored to modulate immune cell activation to promote infection resolution. This perspective highlights the factors leading to infection persistence in the CNS and discusses how novel nanoparticle therapies can be engineered to provide enhanced treatment, specifically through modulation of immune cell polarization.