Abstract
Neurodegenerative disorders represent a growing global health burden and remain largely incurable, with current therapies providing only symptomatic relief and limited disease modifications. A major obstacle to effective treatment is the inability of many neuroprotective agents to reach the brain at therapeutically relevant concentrations due to poor bioavailability and the restrictive nature of the blood-brain barrier. Plant-derived phytochemicals possess well-documented antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory activities; however, their clinical translation has been hindered by physicochemical instability, rapid metabolism, and insufficient brain exposure. This review critically examines nanoengineered delivery systems as a strategy to overcome these limitations and enable the effective brain targeting of neuroprotective phytochemicals. By integrating mechanistic insights with preclinical and emerging clinical evidence, we compared lipid-based, polymeric, vesicular, and dendritic nanocarriers, highlighting how particle size, surface chemistry, and ligand functionalization govern blood-brain barrier transport and intracerebral distribution. Particular emphasis is placed on rational design principles that consistently enhance brain bioavailability and therapeutic efficacy across models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and related disorders. Beyond efficacy, we analyzed key translational challenges, including nanocarrier-associated neurotoxicity, standardization of herbal activities, and regulatory gaps unique to herbal nanomedicines. Collectively, this synthesis reframes nano-phytomedicine not as an incremental formulation upgrade but as a design-driven strategy capable of unlocking the therapeutic potential of phytochemicals for neurodegenerative disease management.