Recent advances in polymeric nanoparticle-mediated drug delivery system across the blood-brain barrier in Alzheimer's...

Alzheimer's disease (AD) is driven by complex and interrelated pathological processes, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, mitochondrial dysfunction, synaptic loss, and chronic neuroinflammation. These multifactorial mechanisms contribute to progressive cognitive decline and limit the effectiveness of conventional therapeutic strategies. Polymeric nanoparticles (PNPs) have emerged as a promising nanotechnological platform for targeted drug delivery in AD, addressing key challenges such as inadequate blood-brain barrier (BBB) permeability, rapid enzymatic degradation of therapeutic molecules, and poor pharmacokinetics. PNPs improve therapeutic efficacy by enabling controlled and sustained drug release, enhancing molecular stability, and promoting selective accumulation in affected brain regions. PNPs can modulate multiple molecular events that underlie AD pathogenesis. They inhibit Aβ fibrillation, reduce tau phosphorylation, scavenge reactive oxygen species (ROS), suppress neuroinflammatory signalling, activate Nrf2-driven antioxidant defense, and regulate microglial polarization toward a neuroprotective phenotype. Additionally, PNPs provide an efficient delivery system for diverse therapeutic agents, including small molecules, peptides, antioxidants, nucleic acids, and natural compounds, which often face challenges in BBB penetration and systemic stability. Recent innovations in surface engineering, biodegradable polymer chemistry, gene-responsive nanocarriers, and stimuli-responsive release systems have further enhanced the potential of PNPs as disease-modifying interventions. Despite these significant advancements, key limitations remain, including uncertainties regarding long-term biosafety, inconsistent biodistribution, challenges in nanoparticle clearance, and translational gaps between preclinical models and humans with AD. Addressing these issues will require interdisciplinary collaboration among materials science, neurobiology, pharmaceutical technology, and clinical research. Overall, this review highlights recent progress, therapeutic mechanisms, and the growing promise of PNP-based brain-targeted nanomedicine as a transformative approach for AD treatment.