**1. Introduction**

7,8-dihydroxyflavone (7,8-DHF) (Figure S1), a naturally occurring infrequent flavone monomeric compound from *Tridax procumbens* and *Godmania aesculifolia*" was authenticated as a high-affinity tropomyosin receptor kinase B (TrkB) agonist [1,2]. It could mimic the physiological roles of brain-derived neurotrophic factor (BDNF) and its associated downstream signaling pathway [3]. Current literature confirms that 7,8-DHF's role in attenuating many BDNF- relevant human illnesses, including Parkinson's disease, Alzheimer's disease, obesity, and depression [4–8]. However, glucuronidation, sulfation, and methylation of

**Citation:** Chen, Y.; Peng, J.; Wang, Y.; Wadhawan, D.; Wu, L.; Gao, X.; Sun, Y.; Xia, G. Development, Characterization, Stability and Bioaccessibility Improvement of 7,8-Dihydroxyflavone Loaded Zein/Sophorolipid/Polysaccharide Ternary Nanoparticles: Comparison of Sodium Alginate and Sodium Carboxymethyl Cellulose. *Foods* **2021**, *10*, 2629. https://doi.org/10.3390/ foods10112629

Academic Editors: Hong Wu and Hui Zhang

Received: 25 September 2021 Accepted: 25 October 2021 Published: 29 October 2021

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7,8-DHF in the intestinal tract or liver caused its extremely low oral bioavailability [9]. In our previous study, we testified that 7,8-DHF's permeability coefficient was lower than 3 × 10−<sup>6</sup> cm/s and had an active efflux mediated by multidrug resistance-related proteins (MRPs, especially MRP 2 outflow) and P-glycoprotein (P-gp) [10]. Thus, the low chemical instability, poor water solubility, and intestinal efflux of 7,8-DHF limit its application as a nutraceutical ingredient in functional food and beverage products.

To resolve the previously mentioned limitations and challenges, constructing an effective delivery vehicle using food-grade polymer is a novel strategy for boosting the utilization of water-insoluble functional components, such as liposomes, microemulsions, nano-emulsions, nanosuspensions, and nanoparticles [11–14]. Among these carriers, protein-based polymers, such as ovalbumin [15], casein [16], gliadin [17], and zein [18], have been utilized to create colloidal delivery systems for phenolic compounds to improve their physicochemical stability, water insolubility, and bioaccessibility. Specifically, these polymers possess several benefits such as high levels of biocompatibility, biodegradability, and label-friendliness.

As a primary storage protein found in corn, zein occupies for approximately 45~50% of total protein content, and has a relatively high percentage of hydrophobic groups. Zein's high level of hydrophobic groups means that it is soluble in 60~95% ethanol-water solutions, but insoluble in water [19]. The varying solubility of zein indicates that zein colloidal delivery systems can be established by antisolvent precipitation (ASP) [20]. Nevertheless, when exposed to a certain temperature, ionic strength, and pH range, zein nanoparticles are highly susceptible to aggregation because of the strong hydrophobic attractions among them. Previous studies have shown that food-grade biopolymers and surfactants can improve the aggregation stability of zein nanoparticles by establishing a protective layer around them. Among these applications, zein-based ternary nanoparticles exhibited more advantages compared to binary nanoparticles. Dai et al. and Wei et al. report that zein/polysaccharide/surfactant ternary nanoparticles functioned as delivery systems for coenzyme Q10 and curcumin, enhancing their structural stability and in vitro bioaccessibility [21,22]. Zhang et al. reported a one-step assembly method for building zein/caseinate/alginate nanoparticles, as propolis were successfully encapsulated in these carriers, their bioaccessibility was improved [23]. In addition, zein/caseinate/sodium alginate nanoparticles were also established to improve the controlled release and physicochemical properties of curcumin [24].

In our previous study, we utilized sophorolipid, a surfactant molecule, to function as fabrication stabilizer for zein binary nanoparticles. These nanoparticles displayed stability at varying salt concentrations (0~100 mM NaCl) and a wide pH range (5~9) [25]. However, at low pH conditions, their stability was low. Therefore, we aim to use biomacromolecules like polysaccharide in this study to construct zein ternary nanoparticles and solve the aforementioned defects. Sodium alginate (ALG) is a natural anionic polysaccharide with a structure of (1 → 4)-b-d-mannan and (1 → 4)-a-l-guluronopyranoys homopolymer sequence isolated from *Phaeophyceae*. ALG can be used as a carrier for biological food components [26]. In addition, sodium carboxymethyl cellulose (CMC) is also a suitable anionic polymer for the delivery of bioactive ingredients [27]. Due to their widespread availability and functional properties, CMC and ALG are favorable candidates for the protection of coated zein/sophorolipid binary nanoparticles when encapsulating 7,8-DHF.

The first objective of our research was to explore the effect of polysaccharides type (CMC and ALG) on the formation and performance of zein ternary nanoparticles. Subsequently, to improve in vitro bioaccessibility and storage stability of 7,8-DHF, zein ternary nanoparticles encapsulation were manufactured. Moreover, the microstructure and chemical structure of these ternary nanoparticles were analyzed by a series of characterization techniques. For precision diet intervention or functional food field, this research provides valuable insights to develop more effective delivery systems for 7,8-DHF, which will allow more 7,8-DHF to be absorbed by the human intestines, exerting greater biological effects for human heath. For functional beverage industry, stable zein-surfactant-polysaccharide delivery systems allow hydrophobic active components, such as 7,8-DHF, to be better dispersed in the water-phase beverage system to develop more functional beverage products.
