Nanoparticles for Drug Delivery Across the Blood-Brain Barrier: A Comprehensive Review of Mechanisms, Platforms, and Translational Frontiers

Central nervous system (CNS) disorders—including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and glioblastoma multiforme (GBM)—impose a mounting global healthcare burden, yet remain poorly treatable due to the blood-brain barrier (BBB), which restricts >98% of small-molecule drugs and virtually all large-molecule biologics from reaching the brain. Engineered nanoparticles (NPs), ranging from 1–1000 nm, have emerged as a transformative solution by exploiting unique physicochemical properties—tunable surface chemistry, high surface-area-to-volume ratios, and dual payload capacity—to circumvent BBB restrictions. This review comprehensively examines nanoparticle-mediated BBB drug delivery, covering the structural biology of the neurovascular unit (NVU), disease-specific BBB heterogeneity, and four major NP platforms: lipid-based (LNPs), polymeric (PNPs), metallic/inorganic (MNPs), and biomimetic cell membrane-coated nanoparticles (BMCNPs). Key transport mechanisms—receptor-mediated transcytosis (RMT), adsorptive-mediated transcytosis (AMT), carrier-mediated transport, and Trojan horse cell-based delivery—are critically evaluated. Advanced strategies including PEGylation, focused ultrasound (FUS), and intranasal delivery are discussed alongside translational evidence across AD, PD, and GBM. Finally, we address the critical barriers to clinical translation—the affinity paradox, post-BBB transport constraints, immunogenicity, scalability, and regulatory hurdles—and propose a precision, disease-informed nanomedicine framework as the path to clinical success.