Safe and reliable entry to the brain is essential for successful diagnosis and treatment of diseases, but it still poses major challenges. As a result, many therapeutic approaches to treating disorders associated with the central nervous system (CNS) still only show limited success. Nano-sized systems are being explored as drug carriers and show great improvements in the delivery of many therapeutics. The systemic delivery of nanoparticles (NPs) or nanocarriers (NCs) to the brain involves reaching the neurovascular unit (NVU), being transported across the blood-brain barrier, (BBB) and accumulating in the brain. Each of these steps can benefit from specifically controlled properties of NPs. Here, we discuss how brain delivery by NPs can benefit from careful design of the NP properties. Properties such as size, charge, shape, and ligand functionalization are commonly addressed in the literature; however, properties such as ligand density, linker length, avidity, protein corona, and stiffness are insufficiently discussed. This is unfortunate since they present great value against multiple barriers encountered by the NPs before reaching the brain, particularly the BBB. We further highlight important examples utilizing targeting ligands and how functionalization parameters, e.g., ligand density and ligand properties, can affect the success of the nano-based delivery system.
Keywords: blood–brain barrier; brain delivery; controlled drug delivery; nanomedicine; nanoparticles; polymers; therapeutics.