Nose-to-Brain Delivery of Polyherbal Nanoformulations in Neurodegenerative Disorders: Translational Strategies and Challenges

Abstract: Neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease represent major global health challenges because they are associated with progressive neurodegeneration, oxidative stress, mitochondrial malfunction, and neuroinflammation. Existing pharmacological therapies are largely symptomatic and do not effectively halt disease progression. In contrast, herbal medicines exhibit multitarget therapeutic effects that modulate a variety of pathological processes related to neurodegeneration. Despite their therapeutic potential, the clinical use of polyherbal compounds is often limited by poor solubility, phytochemical instability, and insufficient penetration across the blood-brain barrier. Advances in nanotechnology-mediated targeted delivery systems are gaining increasing attention to address such challenges. Specifically, polyherbal nanoformulations integrate the synergistic potential of polyherbal constituents with nanocarrier systems such as liposomes, solid lipid nanoparticles, and nanostructured lipid carriers, thereby enhancing neuroprotective properties in preclinical models. Emerging delivery approaches like nose-to-brain delivery methods further enhance brain bioavailability and the clinical translation potential of polyherbal formulations. Although promising, clinical translation remains limited. This review summarizes the current knowledge on polyherbal synergy, nanocarrier-based targeting methods, and nose-to-brain delivery strategies to treat neurodegenerative disorders, highlighting their potential therapeutic applications, underlying mechanisms, translational issues, regulatory factors, and emerging trends such as the use of artificial intelligence to design nanocarriers. Future research priorities and translational challenges necessary for successful clinical application are also discussed.