Engineering Nanoparticles to Cross the Blood–Brain Barrier: Mechanisms, Applications, and Challenges

The blood–brain barrier (BBB) is the principal obstacle to treating disorders of the central nervous system, excluding the majority of small-molecule and virtually all large-molecule therapeutics from the brain parenchyma. Engineered nanoparticles have emerged as a versatile platform for overcoming this barrier, offering tunable size, surface chemistry, and ligand functionalisation to enable brain-targeted drug delivery. This review summarises the physiological and pathological features of the BBB, the design parameters—particle size, surface coating, and targeting ligands—that govern successful crossing, and the principal classes of nanoparticles developed for this purpose. We examine the mechanisms exploited for transport across the barrier, including passive diffusion, receptor- and transporter-mediated transcytosis, adsorptive-mediated transcytosis, and transient barrier modulation, together with the receptor and transporter pathways that each exploits. We then consider applications in CNS therapeutics, with particular attention to recent advances in nanoparticle treatment of brain tumours, before addressing the key challenges and safety considerations—toxicity, immunogenicity, and translational hurdles—that continue to limit clinical adoption. Finally, we highlight future directions, including personalised nanotherapeutics, that may shape the next generation of brain-targeted nanomedicine.