Advances in Novel Drug Delivery Systems for Targeting the Brain: Overcoming Barriers and Enhancing Therapeutic Efficacy.

The blood-brain barrier (BBB) is critical in CNS pharmacotherapy; it blocks the entry of 98 per cent of small-molecule compounds and almost all macromolecules into the brain parenchyma via tight junction complexes, efflux transporter action, and enzymatic breakdown. This review focuses on the mechanistic basis of BBB resistance and analyses the current landscape of new drug delivery systems developed to overcome this barrier. We elaborate on polymeric nanocarriers, lipid-based nanocarriers, exosomes, dendrimers, and metallic nanoparticles, including surface engineering, the possibility of receptor-mediated transcytosis via transferrin, LRP1, and glucose transporter receptors, and known preclinical efficacy in glioblastoma, Alzheimer's disease, and Parkinson's disease. Non-invasive delivery through the nose is evaluated as intranasal delivery because it utilises olfactory and trigeminal receptors to circumvent systemic delivery. BBB modulation mediated by focused ultrasound is mentioned as one of the physical adjuncts to enhance CNS penetration. Clinical translation is poor, even where the preclinical data are positive. Most late-stage failures can be attributed to protein corona formation, anti-PEG immunogenicity, interpatient heterogeneity in the BBB, and manufacturing scalability. These obstacles are critically evaluated with the help of recent clinical trial evidence, where preclinical models cannot be used as predictors of human outcomes. In the future, AI-based nanocarrier design, machine-learning-driven prediction of BBB permeability, and patient-centred nanomedicine platforms will provide a viable pathway to customised CNS therapeutic approaches. Multimodal strategies integrating RMT, stimuli-responsive carriers, and CRISPRbased gene delivery may collectively overcome the translational gap that single-platform approaches have consistently failed to bridge.