Gaoshuang Fu, Mingmin Pan, Qingling Sun, Guangxin Yue, Tong Lei
Recent studies have shown that neuroinflammation plays a critical role in the pathogenesis of Alzheimer's disease (AD), exacerbating disease progression. Due to their multi-target mechanisms and favorable safety profiles, natural products have gradually emerged as a potential therapeutic strategy for modulating neuroinflammation and improving the symptoms in AD. This study aims to review the pharmacological mechanism and clinical application of natural products in the treatment of AD, and explore the drug delivery forms of natural products, such as self-assembly and nanoparticle loading. The natural products targeting neuroinflammation were summarized, such as Ginkgo biloba leaf extract, curcumin and resveratrol, and their mechanisms in ameliorating AD-related cognitive impairment. Additionally, it was highlighted the progress of clinical trials involving natural products for AD treatment, analyzing their potential in improving cognitive function, psychiatric symptoms, and slowing disease progression in AD patients. Finally, the challenges and future directions of natural products in AD therapy were discussed, emphasizing the importance of enhancing their bioavailability and developing novel drug delivery systems. This review may provide a theoretical foundation and practical reference for research on natural products targeting neuroinflammation to improve cognitive impairment and mental symptom in AD. This schematic summarizes the therapeutic mechanism of natural products (e.g., polyphenols, terpenoids) in Alzheimer’s disease (AD) and the role of nanoscale delivery systems. Natural products exert neuroprotective effects by suppressing neuroinflammation, attenuating microglial activation, reducing pro-inflammatory cytokines (IL-1β, TNF-α), and inhibiting amyloid-β plaque and tau tangle pathology. To overcome the blood-brain barrier and enhance bioavailability, carrier-free nanoformulations (e.g., lipid-based nanoparticles, polymeric nanoparticles, dendrimers, and self-assembled nanoparticles) are engineered. These systems leverage small particle sizes, surface modifications, and sustained release profiles to achieve targeted brain delivery. Consequently, localized accumulation of natural products amplifies anti-neuroinflammatory effects, disrupts pathological protein aggregation, and decelerates AD progression, ultimately improving cognitive outcomes. • Systematic review of natural products' pharmacological mechanisms, clinical applications, and nano-delivery strategies for Alzheimer's disease (AD). • Targeted neuroinflammation: summarizes key natural products and their mechanisms in alleviating AD-related cognitive impairment. • Clinical progress: evaluates pivotal trials (e.g., curcumin nanoparticles) and highlights challenges in efficacy standardization. • Critical insights: provides mechanistic understanding and translational perspectives for natural product-based therapies targeting AD symptoms.