Combined Enzyme- and Ultrasound-Assisted Extraction of Botanical Bioactives for Nutraceutical Ingredients: Mechanisms, Process Design, Scale-Up and Safety

Ultrasound-assisted extraction is widely promoted as a green technology for botanical ingredients, but two recent studies expose its limits. Probe sonication of date palm seed recovered free and soluble-conjugated polyphenols efficiently yet failed to release insoluble-bound polyphenols, indicating that cavitation does not cleave the covalent links between phenolics and the cell wall; and a toxicity review found no direct evidence of toxic compound formation but noted few industrial-scale data and a need for experimental safety studies. This narrative review examines whether combining enzymes with ultrasound addresses these gaps. Cell-wall-degrading enzymes hydrolyse the polysaccharide and ester bonds that retain bound phenolics and other constituents, while ultrasound increases enzyme access, mass transfer and, under mild conditions, enzyme activity; synergy was observed when ultrasound was applied during, rather than before or after, enzymatic hydrolysis of complex plant matrices. The review compares treatment sequences and operating windows, discusses scale-up of probe and flow-cell systems, and sets out safety and quality considerations specific to the combination, including enzyme residues, deglycosylation, radical formation and co-extraction of natural toxicants. A reporting standard based on delivered acoustic energy, enzyme activity units and fraction-resolved analysis is proposed.