Natural deep eutectic solvents for sustainable bioactive compound extraction: Fundamentals, emerging technologies, current scale-up challenges, and future industrial perspectives

The global transition toward sustainable manufacturing has intensified interest in eco-friendly solvent systems for extracting bioactive compounds from natural matrices. Conventional petroleum-derived solvents, such as hexane, methanol, and acetone, remain efficient but increasingly criticized for their volatility, toxicity, and poor biodegradability, all of which contravene the principles of green chemistry and circular bioeconomy. Over the past decade, alternative solvent classes including ionic liquids (ILs), deep eutectic solvents (DESs) and their natural analogues- natural deep eutectic solvents (NADESs), supercritical fluids (SCFs), and hybrid co-solvent systems have emerged as promising substitutes. As aforementioned, NADESs have attracted particular attention for their renewable origin, molecular tunability, low volatility, and capacity to dissolve structurally diverse phytochemicals such as polyphenols, flavonoids, alkaloids, carotenoids, and essential oils. Despite these advances, significant barriers still impede industrial adoption. The high viscosity and mass-transfer resistance of NADES, limited recyclability, incomplete toxicological profiling, and lack of standardized metrics for solvent “greenness” continue to challenge scalability. Moreover, techno-economic feasibility, process integration, and regulatory acceptance remain insufficiently investigated at the pilot and commercial levels. This review provides a comprehensive and critical evaluation of recent progress in NADES-based extraction of bioactive compounds, focusing on their physicochemical properties, molecular interaction mechanisms, extraction kinetics, and environmental performance. Key challenges related to process optimization, solvent recovery, life-cycle assessment, and safety evaluation are discussed. Finally, strategic perspectives are proposed to guide the development of next-generation natural eutectic solvent systems that are not only efficient and selective but also safe, economically viable, and aligned with sustainable industrial practices.