Edible Nanoencapsulation Vehicles for Oral Delivery of Phytochemicals

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Edible Nanoencapsulation Vehicles for Oral Delivery of Phytochemicals: A Perspective Paper Jie Xiao, Yong Cao, and Qingrong Huang J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.7b02128 • Publication Date (Web): 24 Jul 2017 Downloaded from http://pubs.acs.org on July 28, 2017

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Journal of Agricultural and Food Chemistry

Edible Nanoencapsulation Vehicles for Oral Delivery of Phytochemicals: A Perspective Paper Jie Xiao † Cao Yong † and Qingrong Huang ‡,*

†

Department of Food Science, College of Food Science, South China Agricultural

University, Guangzhou 510640, China ‡

Department of Food Science, Rutgers University, 65 Dudley Road, New Brunswick,

New Jersey 08901, USA * To whom correspondence should be addressed. Tel: (848)-932-5514. Fax (732) 932 6776. Email:[email protected]

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ACS Paragon Plus Environment


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ABSTRACT

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Edible nanoencapsulation vehicles (ENVs) designed for the delivery of phytochemicals have

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gained increasing research interest. The major driving force for this trend is the potential

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bioavailability enhancement effect for phytochemicals when delivered via ENVs. ENVs affect

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the bioefficacy of phytochemicals by influencing their dispersion and gastrointestinal stability,

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rate and site of release, transportation efficiency across endothelial layer, systemic circulation

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and biodistribution, as well as the regulation of gut microflora. Enhanced bioefficacy can be

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achieved by rational design of the size, surface property, matrix materials and compartment

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structure of ENVs according to properties of phytochemicals. Future investigations may lay

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particular emphasis on examining the relevance between results gained by in vitro digestion

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simulations and those obtained via in vivo ones, structural evolutions of ENVs during digestion

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and absorption, impacts of ENVs on the metabolism of phytochemicals, and using ENVs for

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deciphering the reciprocal interactions between phytochemicals and gut microbiota.

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KEYWORDS: edible nanoencapsulation vehicles, phytochemicals, bioefficacy, digestion,

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structural changes, gut microflora

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Introduction:

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Phytochemicals or phytonutrients are secondary metabolites widespread in fruits, vegetables,

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and herbal extracts, their varieties span a wide range of chemical structures such as phenolic

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acids, indoles, alkaloids, isothiocyanates, phytosterols and saponins.1-4 Although not essential for

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growth and development, they have received constant research fever due to their well-

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documented beneficial effects in health maintenance and disease risk reduction.5-7

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Phytochemicals in the native format or their metabolites exert health beneficial effects through

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mechanisms involving direct radical scavenging effect, inhibition of the assembly of microtubule

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and microfilament, metal chelation, protease inhibition, etc. 8, 9

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After oral intake, phytochemicals are recognized and processed by human body as

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xenobiotics, five consecutive events occurred thereafter10: (i) Digestion and degradation along

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the mouth, stomach, small and large intestine; (ii) Absorption from the digestive tract into the

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blood or lymph circulation; (iii) Biodistribution via diffusion or transportation from the

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intravascular space to extra-vascular space or body circulation; (iv) Metabolism in body tissues

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by biochemical conversion or degradation; (v) Excretion via renal, biliary or pulmonary

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pathways. During this process, the maximum plasma level of phytochemicals (cmax), the time to

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reach the maximum concentration in the blood (tmax), and the area under the curve of plasma

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levels vs. time (AUC), are characterized as “bioavailability”.14-16 And “bioaccessibility”, the

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potentially absorbable amount from the small intestinal epithelial cell line, is defined as a

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prerequisite for bioavailability. Since the minimum dosage required for phytochemicals to exert

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biological effects in vivo is evaluated by “bioefficacy”, usually demonstrated by short-term

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changes in biomarkers such as liver function, plasma lipid profiles, blood pressure, plasma

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glucose and plasma antioxidant activity,11-13 bioefficacy are thus influenced by both chemical

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nature of phytochemicals and biochemical activities happened during the above-mentioned

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physiological processes. And “bioavailability” and “bioaccessibility” are commonly measured to

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serve as references for the predicting of “bioefficacy”.

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In the following sections, processes and factors that affect bioefficacy of phytochemicals will

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be summarized, current understanding on how edible nanoencapsulation vehicles (ENVs)

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influence the bioefficacy of phytochemicals during oral administration and corresponding

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challenges and perspectives will be elaborated.

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Processes and factors that affect bioefficacy of phytochemicals

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In reality, the occurrence of phytochemicals or their metabolites at the systemic and tissue

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levels may fall in the micromolar range, and their efficacies are thus limited due to insufficient

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dose efficiency after oral administration.

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poor water solubility, their dispersion ability in stomach and small intestine are limited in the

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first place. Phytochemicals that form insoluble-complex or subject to degradation during

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digestion process also exhibit a limited bioaccessibility; When absorbed through the gut, small

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intestinal enterocytes host the cellular uptake, efflux pumping and phase I & II metabolism

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processes, the combined effects determined the bioaccessible amount of phytochemicals;

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Afterward, the absorbed phytochemicals together with those metabolites of enterocyte pass next

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into hepatocytes where extensive phase I and phase II biotransformation reactions take place.

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Such processes are on the one hand necessary for certain phytochemicals to transfer from

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precursors to active formats, on the other hand dramatically diminished the bioavailability of

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phytochemicals such as polyphenols;18-20 For certain lipophilic phytochemicals, these routines

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can be escaped by lymphatic absorption pathway.

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parent phytochemicals or their metabolites exert functional activities through circulation and

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As presented in Figure 1, for phytochemicals with

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After entering the systemic circulation,


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distribution in body tissues, where bioefficacy of phytochemicals are more often than not to be

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further decreased if they were quickly excreted;22 Lastly, the unabsorbed phytochemicals

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together with their digestive residues then reach to the colon, where they may be further broken

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down by the gut microflora and affect the bioafficacy indirectly.

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Edible nanoencapsulation vehicles (ENVs) for delivery of phytochemicals

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Edible nanoencapsulation vehicles (ENVs), utilizing the “generally recognized as safe”

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(GRAS) ingredients (various lipid, polysaccharides, proteins and biodegradable polymer that

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featured on the “GRAS” list) as building materials, are encapsulation and delivery vehicles with

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at least one dimension in the size range of 1-100 nm. Rational design of ENVs with controlled

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sizes, surface properties, matrix materials and compartment structure have been utilized as

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effective strategies for enhancing the bioefficacy of phytochemicals.23, 24 ENVs with different

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structural characteristics, such as nanoliposome, micelle, nanoemulsion, solid lipid nanoparticles,

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polymeric nanoparticles (nanospheres and nanocapsules), protein-polysaccharides complex

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coacervation, cyclodextrin inclusive and polymeric nanogel, vary in the phytochemical loading

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process, encapsulation efficiency, stability during digestion, drug release mechanism, and

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therefore bioefficacy enhancement principles (Table 1).

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The bioefficacy enhancement effects of ENVs are associated with their particle size, surface

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properties, matrix materials and compartment structure.25 In general, ENVs affect the bioefficacy

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of phytochemicals by influencing the dispersion and gastrointestinal stability, the rate and site of

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release, the transportation efficiency across endothelial layer, the systemic circulation and

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biodistribution, as well as the regulation of microflora metabolism processes.

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1) Influences of ENVs on dispersion and gastrointestinal stability

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The nano-scale particle size, usually in the range of tens to hundreds of nanometers, is the

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foremost characteristic property of ENVs. Such property is essential for them to remain stable in

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dispersion system due to the large surface area per unit volume. Besides, ENVs in format of

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polymeric nanoparticles, solid lipid nanoparticles or nanoemulsion further ensure the colloidal

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stability by introducing inter-particle repulsion forces and/or interfacial tension decreasing

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compounds.26-29 Both properties lift their chances of interacting with intestinal lining and

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facilitate the cellular uptake process thereafter. Loading phytochemicals within such ENVs has

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been one of the most popular research strategies to enhance dispersion property of initially water

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insoluble phytochemicals. For instance, kafirin protein based nanoparticles,

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nanocapsules,30 cyclodextrin inclusive, 31 and hydrophobically modified starch based micelles32

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have all been adapted to lift the bioavailability of curcumin by enhancing its aqueous dispersion

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property.

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casein based

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Furthermore, the physical barrier property introduced by ENVs provides additional

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protective effects to sensitive phytochemicals through the digestive tract. 33 For example, free

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epigallocatechin gallate (EGCG) and catechin rapidly degraded under alkaline small intestinal

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fluids, encapsulation within caseinophosphopeptides/chitosan nanoparticles effectively prevented

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EGCG from oxidation,34 and catechin loaded liposomes lowered the degradation risks in

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simulated intestinal fluid.35 Except for polymeric nanoparticles, the inner compartment of water-

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in-oil-in-water double emulsions, solid lipid nanoparticles and polymeric nanogel offer shielding

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effects towards vulnerable phytochemicals to adversary pH, salt or enzymatic conditions of GI

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tract.

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2) Influences of ENVs on release profile of phytochemicals

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Overall, the digestion and release of phytochemicals in native state can be regarded as a

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dissolution process, where the solubility, stability and penetration property of phytochemicals in

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the gastrointestinal (GI) tract define key factors affecting its bioaccessibility thereafter. Once

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encapsulated within ENVs, physiological processes involve the digestion of ENVs, the release of

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phytochemicals and changes in chemical/physical state of phytochemicals. Depending on the

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chemical nature of matrix materials, the digestion site and rate of ENVs are predetermined in the

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first place (Figure 2). To be specific, the integrity of proteins based ENVs readily destroyed by

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pepsin in stomach. While starch based ENVs are subjected to amylase digestion during mouth,

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the majority of polysaccharides based ENVs experience degradation in small intestinal digestion.

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Non-starch polysaccharides, such as chondroitin sulfate, pectin, chitosan, guar gum, alginate, etc.,

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and resistance starch retain structural integrity until reaching the colon due to lack of digestive

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enzymes in stomach and small intestine, they thus serve as popular matrix candidates for colon-

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targeted ENVs. Structural collapse of protein-polysaccharides complex based ENVs and

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shrinkage or swelling of hydrogel based ENVs can be triggered by changes in pH value and salt

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concentration. 33 As for ENVs consisting of lipid phase, the release of phytochemicals occurred

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in small intestine along with the release of digestion byproducts of triglyceride. Biodegradable

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polymer (e.g. poly(lactic acid) (PLA), poly(lactic-co-glycolic acid) (PLGA)) based ENVs

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possess limited digestion rate in GI tract, and are thus more easily made their way to

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systemic circulation in intact format.

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The fabrication processes of ENVs also exert direct influences on the release profile of

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phytochemicals. Factors such as the drug loading method, loading efficiency and size of ENVs

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all work together to shift the partitioning equilibrium of phytochemicals between the

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encapsulation matrix and surrounding digestion fluids. For instance, the nanocapsule-based

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delivery vehicles diminish the burst release of phytochemicals remarkably as compared to a

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nanosphere-based delivery vehicle when both formulations possess the same encapsulation

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efficiency. And ENVs with higher loading efficiency and smaller vehicle size, more often than

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not, compromise with a higher burst release rate.36 Furthermore, the structural choice of

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encapsulation compartment actively tunes the release profile.15,37 Core-shell nanoparticles,

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double emulsions, gelled networks, multiple coating systems and “prodrug delivery systems”

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(where phytochemicals are conjugated with azo or glucoronic acids-containing polymers before

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or during the encapsulation processes, and the release of active moiety is triggered by enzymatic

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hydrolysis) are emerging approaches to retard the release rate of phytochemicals. Finally,

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accompanied with the release process, phytochemicals initially loaded within ENVs may

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undergo changes in physical dispersion state. A most striking example is the release of lipophilic

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phytochemicals from the lipid phase of ENVs, where lipophilic phytochemicals migrate into

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micelles formed by free fatty acids after the digestion of triglycerides, which facilitates the

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solubilization and subsequent cellular transportation process. 29,38,39

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3) Influences of ENVs on transportation and metabolism across endothelial layer

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The endothelium comprises a monolayer of endothelial cells that line blood and lymphatic

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vessels, through which phytochemicals enter into systemic circulation. The transportation of free

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phytochemicals cross the epithelial cell layer relies on the residence time and passive diffusion.

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For phytochemicals encapsulated within ENVs, ENVs and/or their derivative structures after

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digestion exert further influences on bioavailability by altering the residence time, the

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transportation efficiency and/or pathways (Figure 3).

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ENVs with initial size < 20 nm (or obtained after digestion) lift the paracellular permeability

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of phytochemicals. Coating materials of ENVs such as chitosan and chitosan derivatives possess

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the mucoadhesive and tight junction opening effects which prolong resistance time and enhance

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paracellular transport.40-43 For particles (or vehicles) with average size of 20 nm - 1µm, cellular

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uptake is conducted by transcellular endocytosis on the surface of enterocytes. And ENVs

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possessing positive charged groups and/or functional groups capable of forming hydrogen bonds

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with mucosal surfaces facilitate the temporary retention to mucosal membranes, although the

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same effects could also lead to reduced penetration efficiency across the mucus.44 By

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incorporating cell-penetrating ligands such as transferrin, vitamin B12, penetratin and

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oligoarginine to ENVs, the receptor-mediated cell endocytosis lead to enhanced transmembrane

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transport efficiency. With regard to the efflux pumping effect resulting from the P-glycoproteins

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(P-gp) on apical membranes of epithelial cells, higher bioaccessibility can be achieved by

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introducing efflux pump inhibitors, such as Tween 80, hyaluronic acid, chitosan, gellan gum and

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sodium alginate, as surface materials.45 Finally, when transport across the endothelial layer,

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phytochemicals loaded ENVs generally end up in endosomes or lysosomes followed by

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extensive Phase I (e.g. oxidation, reduction and hydrolysis) and Phase II (e.g. conjugation)

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enterocyte-based metabolism. In this process, ENVs contribute to enhanced bioefficacy by

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affecting the exposure time of phytochemicals to metabolizing enzymes in enterocyte. 46 As we

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have reported, the enhanced cellular antioxidant activity of EGCG after encapsulation within

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biopolymer based nanoparticles was probably due to the minimized metabolism of EGCG by

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corresponding glycosylase and methylase during the cellular transportation process. 47

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For highly lipophilic phytochemicals that have a log P (the logarithm of the oil-water

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partition coefficient (P) of phytochemicals) > 5 and a long-chain triglyceride solubility

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>50 mg/g, they may transit across the enterocyte and form chylomicrons with enterocyte

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lipoproteins,48 which then enter the systemic circulation via mesenteric lymph ducts and thoracic

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ducts. As a result, highly lipophilic phytochemicals manage to avoid hepatic first pass

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metabolism. Since lipid digestion products are needed to stimulate the production of

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chylomicrons, the degree of lymphatic transport strongly correlates with the triglyceride content

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of the lymph. ENVs with lipid phase incorporated including emulsions, liposomes, solid lipid

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nanoparticles, are therefore particularly effective delivery formats in mimicking the

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physiological conditions favorable for lymphatic absorption.49, 50 Additionally, the increase in

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membrane fluidity introduced by lipid based ENVs contribute further to the enhanced

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transcellular absorption efficiency. Several in vitro lipolysis case studies have confirmed that

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lipophilic compounds in emulsified state were digested and became bioaccessible much faster

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than their oil suspension state. 29,38,49

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4) Influence of ENVs on systemic circulation and biodistribution of phytochemicals

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Presystemic degradation of orally administrated ENVs in both gastrointestinal tract and

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endothelial cells play major roles in eliminating ENVs. Only digestive residue of ENVs find

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their way to systemic circulation and experience subsequent hepatic and/or systemic exposure.51

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Unlike the slow elimination and tissue accumulation properties of inorganic nanoencapsulation

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vehicles, ENVs usually have fast clearance rate by the mononuclear phagocytic system (MPS).25

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By rational design, the pharmacokinetic profile of phytochemical in ENVs during body

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circulation is controllable to a certain extent. In practice, hydrophilic coating of PEG acts as

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steric barrier to increase the circulation time of ENVs in blood. Take liposome coated with PEG

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for instance, PEGylation protects liposomes from opsonization and results in prolonged

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circulation time.22, 52 Similarly, biological capping materials such as chitosan or BSA protect

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ENVs from fast clearance by mimicking the physiological environment.53 The formula design of

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ENVs also actively alter the biodistribution behavior of phytochemicals in different tissues and

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organs. By far, in vivo investigations suggested that particulate ENVs with proper surface charge

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and particle size could navigate towards the leaky vasculature of cancerous tumors and passively

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target the desired cancerous tissue. 54And phospholipid composition as well as concentration of

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emulsifiers of emulsion based ENVs tune the biodistribution profile via affecting the

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lipophilicity, plasma binding properties of phytochemicals.

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gained by introducing magnetic nanoparticles, surface chemical modification and biorelevant

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ligands (oligosaccharides, antibodies, polypeptides or viral proteins, etc.) to ENVs. 56-58

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5) Influences of ENVs on the microflora metabolism process of phytochemicals

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More precise control could be

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The unabsorbed phytochemicals loaded ENVs in upper GI tract will then proceed to the large

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intestine, where they undergo further metabolism by the gut microflora via esterase, glucosidase,

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demethylation, dehydroxylation and decarboxylation activities. And the ability of certain

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phytochemicals to interfere with microbial signaling has been recognized as a critical factor in

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evaluating their actual bioefficacy. Such effect is exerted either through the absorption of colonic

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metabolites of phytochemicals or modulation in gut microbial populations.59 Take polyphenol

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compounds for example, only 5–10% of the orally intake polyphenol is absorbed in the upper GI

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tract with the majority of them being accumulated in the large intestinal lumen and subjected to

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enzymatic activities of gut microbial community.60 The subsequently produced phenolic

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metabolites then absorbed through colonic epithelium into the systemic circulation to exert their

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bioactivities.61-64 Phytochemicals and their derived products can also affect the intestinal

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ecology, for example, the intake of flavonol-rich foods modified the composition of gut

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microbiota, exerting prebiotic-like effects.65

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Perhaps, the most remarkable influence of ENVs exerted on the microflora metabolism

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process of phytochemicals lies in the change in distribution proportion of phytochemicals

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between upper and lower GI tracts (Figure.4). For ENVs aiming to improve the absorption rate

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of phytochemicals in upper digestion tract, the available amount of phytochemicals reaching to

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colon is reduced. Herein, the “nanoparticulate curcumin delivery system” is one of the most

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appropriate examples. Without the nanoencapluation treatment, the majority of orally consumed

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curcumin would end up in lower GI tract due to its poor solubility and low transcellular

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efficiency, whereas curcumin experienced a dramatic increase in adsorption efficiency in upper

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GI tract after the nanoencapsulation treatment.

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riboflavin, quercetin, rutin and anthocyanins, that rely on the gut microbial metabolism to

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convert into more potent bioactive compounds, prevention of absorption and degradation in

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upper GI tract is desirable.65 Colon-targeted ENVs are thus fabricated using digestion resistant

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materials and/or with multilayered architectures (e.g. nanoparticles in microparticle,

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nanoparticles in hydrogel) to minimize the absorption and degradation in upper GI tract. And the

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design guideline of colon-targeted ENVs also includes a colon-specific release profile triggered

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by osmotic, pH and microflora conditions in colonic mucosa. Due to the low colonic luminal

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fluid volume, higher viscosity, and a neutral pH as compared to the upper GI tract, the low

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solubility as well as mucosal absorption of phytochemicals limits their colonic absorption.

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Therefore, even for hydrophobic phytochemicals, where the GI absorption rate is poor by

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nature, ENVs is necessary in that they minimize phytochemicals from possible degradation in

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upper GI tract, lift the dispersion property in colonic luminal fluid, promote the adhesion and

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adsorption in ileum and colon mucusa.

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For phytochemicals, such as resveratrol,

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Apart from the influence on available amount of phytochemicals subjected to microbiota

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methabolism, the presence of matrix materials of ENVs that co-delivered to colon exert further

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impacts on intestinal metabolism. Non-starch polysaccharides, such as cellulose, dextrins,

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chitins, pectins and waxes not only modulate the transit time through the gut but also induce

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changes in bacterial populations during partially bacterial fermentation. And microbiota derived

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products from fibers and lipids by themselves contribute to the lifted bioefficacy via protection

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against gastrointestinal disorders and pathogens, modulating immune responses, reduction in

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plasma triacylglycerol, etc.67-69

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Challenges and perspectives

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For research trends in fabrication strategies of ENVs, combining multiple structural designs,

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which either strengthen the property of one ENV or combine benefits of two or more ENVs, is

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an attractive approach for maximized effect.72-75 In the realm of target delivery, though materials

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and fabrication strategies that allow for the creation of ENVs with design freedom constantly

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growing, effective target-delivery has not yet been developed. Compared to intravenous drug

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delivery systems, orally administrated ENVs can hardly be considered as real candidates for

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tissue targeted delivery in the near future. Such an inevitable drawback roots from the high

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presystemtic degradation rate of the majority of ENVs.

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Currently, in vitro digestion simulation models of phytochemicals loaded ENVs serve as

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cost-efficient tool for predicting the oral bioavailability of phytochemicals loaded ENVs, and are

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quite efficient for comparative studies among different ENVs. The emerging trend has now

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shifted from the bottle-based static gastrointestinal systems to the computer-controlled dynamic

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gastrointestinal systems, an attempt to avoid oversimplification of the three-dimensional

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structure and mechanical movements of the gastrointestinal tract. As for cellular transportation

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investigations, in view of the fact that the widely adapted cell layer covered models (e.g., Franz

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diffusion cells, transwell-systems and Ussing chambers) fail to mimic the intestinal environment

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due to their lack of mucus producing property, cell layer models with mucus secreting

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functionality are proposed. Compiling data from relevant studies and elucidating the relevance of

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in vitro studies to in vivo pharmacokinetic trials are worth trying research attempts.

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When evaluating effects of ENVs on bioefficacy of phytochemicals, extra attention should be

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paid on experimental design. Firstly, a reliable bioefficacy assessment should consider possible

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changes in the structure of ENVs under real digestion situation. To be specific, when mixed with

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digestion fluid, the dilution effects on ENVs, such as micelles, liposomes and nanoemulsion, are

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not negligible since their structural integrity relies on maintaining surfactant concentration within

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a narrow range. Effects of pH, ions and enzymes in the GI tract on stability of ENVs also pose a

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non-negligible impact. Therefore, studies targeting structural evolution of ENVs in complex

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matrices (i.e. real food matrices), rather than in simplified model systems, hold more practical

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significance. Moreover, when conducting comparison experiments on bioefficacy between free

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phytochemicals and ENVs encapsulated ones, possible differences in pharmacokinetic profiles of

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phytochemicals should be taken into account. For example, the existence of ENVs may change

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the internalization speed of phytochemicals, according to which the sampling points for

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biomarker detection should be adjusted accordingly.

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In addition, metabolic conversion is known as a major factor affecting phytochemical

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bioavailability. Currently, little is known about how the cellular signaling pathways differ from

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free phytochemicals and impacts of co-existence of ENVs on the metabolism of phytochemicals

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remain unanswered. There has been reports claimed that the coexistence of proline-rich proteins

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are capable of binding gallated catechins like epigallocatechingallate and convert them into non-

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gallated catechins like epigallocatechin by tannase, thus enhancing epigallocatechin

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bioavailability.70 Cleary, the hypothesis that “interaction between phytochemicals and matrix

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material of ENVs may exert effect on their metabolism and thus bioefficacy” needs further

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investigation.71 Intensive researches aiming to elucidate the correlation between the formula of

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ENVs and their metabolic profiles and biodistribution behaviors should be conducted to serve as

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a guideline in the rational design of ENVs with maximized bioefficacy and predictable in

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vivo properties.

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Lastly, not only original phytochemicals but also their microbial metabolites should be taken

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into account when assessing the bioefficacy of phytochemicals. And if the role of gut

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metabolism is considered, we have to redefine the current definition of “bioavailability” and

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“bioaccessibility”, both emphases the absorption in upper GI tract. Such concept is vital in

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rational design of ENVs based on the nature of phytochemicals. ENVs aiming at improving the

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absorption through the upper GI tract may not serve as the gold standard anymore, since for

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phytochemicals whose high bioefficacy root from gut metabolism, limited absorption in the

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upper GI tract is desirable. Currently, the reciprocal interactions between phytochemicals and gut

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microbiota, the mechanisms of action, and the consequences of these interactions on bioefficacy

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are still poorly understood. And the role of nanoencapsulation on the metabolism of

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phytochemicals by microflora posts additional challenges on the already complicated situation.

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To date, the assessment of effects of nanoencapsulation on gut microbiota metabolism of

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phytochemicals in human gut has been rarely reported. Comparison studies conducted between

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phytochemicals delivered with or without accompanied ENVs will shed new light on deciphering

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the inter-relationship between phytochemicals and gut microbiota.

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Overall, encapsulate phytochemicals within appropriate ENVs lift the bioavailability of

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phytochemicals via: i) protect sensitive phytochemicals from degradation during storage and

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gastrointestinal digestion; ii) solubility enhancement; iii) prolonged contact time with the

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intestinal wall; iv) increase the mucus penetration and intestinal permeation; v) facilitate cellular

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uptake; vi) prolong residence time within the body circulation; vii) controlled release rate and

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site; viii) alter the microflora metabolism. The initial physicochemical aspects of ENVs, their

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digestion stability, endothelial transportation efficiency, metabolism and interactions with gut

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microbiota, govern the bioefficacy of phytochemicals. It can be foreseen that the contribution of

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ENVs will not limit to the bioefficacy enhancement of phytochemicals, but also offer a powerful

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tool to decipher the current mystery of reciprocal interactions between phytochemicals and gut

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microbiota.

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Acknowledgment

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Authors acknowledge the financial support for the first author from the China Scholarship

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Council.

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558

Figure Captions

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Figure 1: Processes (in blue) and key factors affecting bioefficacy (marked by bullet points) of

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phytochemical after oral intake.

561

Figure 2: ENVs exert influences on release profile of phytochemicals through programed

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Figure 3: ENVs exert influences on transportation across endothelial layer of phytochemical via

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Figure 4: ENVs exert influences on the microflora metabolism process of phytochemical by 1)

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569

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27



Page 28 of 32

Table 1. Non-exhaustive categories of edible materials based nanoencapsulation vehicles for the delivery of phytochemicals Nanoencapsulation Systems Nanoliposome: bilayer structure composed of phospholipids (

Edible Nanoencapsulation Vehicles for Oral Delivery of Phytochemicals

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