###### Abstract  
Mangosteen (_Garcinia mangostana_ L.) peel is a potential source of phenolic compounds with beneficial properties. Natural deep eutectic solvents (NaDES) have been considered an environmentally friendly and cheap alternative to conventional organic solvents. In this work, a green extraction methodology was developed using ultrasound-assisted extraction (UAE) and NaDES for the extraction of antioxidant non-extractable polyphenols (NEPs) from mangosteen peel. To select the best NaDES to extract NEPs from mangosteen peel, seven NaDES were studied. Antioxidant capacity and total phenolic and proanthocyanidin contents were determined for the extracts. The molecular weights for the NEPs present in those extracts were evaluated by size exclusion chromatography. Experimental results showed that choline chloride-lactic acid (1:2) was the NaDES allowing the highest antioxidant proanthocyanidin content in the extracts. A Box-Behnken experimental design was employed to optimize the main parameters in UAE with NaDES: water percentage, ultrasound amplitude, and extraction time. The optimal extraction conditions were 18.8% (\(v/v\)) water, 60% ultrasound amplitude, and 15 min as the extraction time. In addition, the cytotoxicity of the NEP extracts obtained under optimal extraction conditions was evaluated. Results indicated for the first time that the use of NaDES in combination with UAE could be a sustainable alternative for the extraction of antioxidant NEPs from mangosteen peel for important applications in the food, pharmaceutical, agrochemical, and cosmetic fields, as the extracts presented low cytotoxicity. n _Applied_  
16 June 2021  
18 June 2021  
Multi-scale 2021  
discarded and considered a waste [4; 5]. The peel from this fruit is a potential source of antioxidant phenolic compounds such as phenolic acids, tannins, xanthones, and anthocyanins [6; 7; 8]. Studies about the presence of phenolic compounds in mangosteeen peel have only been focused on the extraction of polyphenols through the use of aqueous-organic solvents without paying enough attention to bound polyphenols that remain in the residues after solvent extraction [5; 9; 10; 11]. These underestimated compounds with interesting biological properties are known as non-extractable polyphenols (NEPs) [12]. NEPs include high-molecular-weight polymeric polyphenols and individual low-molecular-weight phenolic compounds, bound to dietary fiber or other macromolecules through hydrophobic interactions and hydrogen and covalent bonding [13; 14]. As far as we know, the presence of NEPs has not been yet studied in mangosteeen peels. In order to carry out the extraction of NEPs from natural sources, acid, alkaline, or enzymatic hydrolysis of the extraction residue is needed to release these compounds from macromolecules. However, many phenolic compounds are sensitive at very high pH conditions during acid and alkaline hydrolysis, which might change the structure of NEPs, breaking down non-covalent complexes and making it difficult to recognize their original conformations. In addition, these three treatments should be employed carefully because there is a possibility of breaking covalent bonds in the polyphenols [15]. In the last few years, society has increased its interest in the development of green methodologies due to higher awareness about the environment. Therefore, one of the goals of this work was to contribute to a more sustainable extraction process following green chemistry principles, in which the extract was obtained while having the lowest environmental impact (minimizing the employ of organic solvents and energy) [16]. In that sense, novel solvents known as natural deep eutectic solvents (NaDES), which can replace the use of organic solvents in the extraction of bioactive compounds due to their great bio-affinity and little toxicity, have been recognized as sustainable and safe [17; 18]. Therefore, these solvents are appropriate for being used in pharmaceutical, cosmetic, agrochemical, and food applications [17].