Alzheimer’s disease: unraveling role of xanthone derivatives and nanocarriers

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, memory impairment, and neuronal loss. Xanthones, a class of polyphenolic compounds, have shown potential neuroprotective effects in AD due to their antioxidant, anti-inflammatory, and acetylcholinesterase inhibitory properties. However, their therapeutic use is limited by low bioavailability and restricted blood-brain barrier (BBB) penetration. This review highlights the novelty of bridging the therapeutic findings of xanthone derivatives with brain-targeted nano-based delivery systems, while identifying gaps for pre-clinical development. A literature review was conducted focusing on the pathophysiology of AD, current therapeutic strategies, the pharmacological properties of xanthone derivatives and recent advancements in nano-based drug delivery systems for xanthone delivery to the brain. The literature search was performed across the PubMed database to identify relevant articles published until January 2025. Evidence from preclinical studies suggests that xanthone derivatives possess multiple neuroprotective properties that can weaken the AD pathophysiology. These compounds can reduce oxidative stress, suppress neuroinflammatory responses, and improve neurotransmission. Besides improving the solubility, recent nanoformulations of α-mangostin, particularly polymer nanoparticles, have demonstrated the potential to overcome the BBB through the enhancement of low-density lipoprotein receptor expression in microglia. Animal studies show improved cognitive outcomes and neuroprotection when xanthones are delivered via nanocarriers, highlighting their disease-modifying potential. Xanthone-loaded nanocarriers represent a promising disease-modifying strategy for AD as they enhance bioavailability and therapeutic outcomes. Future validation of nanoformulations through clinical trials and development of multi-targeted approaches paves the way for innovative and patient-centered neurotherapies, holding significant promise for AD treatment.