A multifaceted review on extraction optimization, nanoformulation, and chemical modification approaches to enhance the yield, bioavailability, and health effects of xanthones

Xanthones, a class of polyphenolic bioactive compounds found abundantly in nature, possess a broad spectrum of pharmacological activities, including anticancer, anti-inflammatory, and antioxidant effects. Despite their therapeutic promise, their clinical translation is limited by poor solubility, low bioavailability, and challenges associated with their efficient extraction. This review critically evaluates the current strategies aimed at overcoming these limitations through extraction optimization, nanocarrier-based delivery systems, and chemical modifications. Nanotechnology-based formulations, such as polymeric nanoparticles, lipid-based carriers, nanoemulsions, nanomicelles, and inorganic/hybrid systems, have significantly enhanced the solubility, stability, and cellular uptake of xanthones, with examples like α-mangostin nanomicelles and mangiferin-loaded nanoemulsions demonstrating potent anticancer activity in preclinical models. Concurrently, green extraction technologies, including supercritical fluid extraction, deep eutectic solvents, ultrasound-assisted methods, and microwave-assisted methods, have surpassed traditional solvent-based techniques in both yield and environmental sustainability. Chemical modifications, such as glycosylation and esterification, exemplified by mangiferin monosodium salts, further improve the water solubility and pharmacokinetic profiles, enabling more targeted therapeutic applications. Nonetheless, challenges remain, particularly in scaling extraction techniques, ensuring the long-term stability of nanoformulations, and conducting extensive human trials. Future perspectives should emphasize the integration of xanthones with other therapeutic agents, development of targeted drug-delivery systems, conjugation of xanthone-based nanocarriers with ligands for tumor-targeted therapy and/or integration with AI-based formulation optimization to fully realize their clinical potential.