Accepted Manuscript

The intelligent delivery systems for bioactive compounds in foods: Physicochemical

and physiological conditions, absorption mechanisms, obstacles and responsive
strategies

Jingjing Chai, Ping Jiang, Pengjie Wang, Yumeng Jiang, Dan Li, Weier Bao, Bingxue
Liu, Bin Liu, Liyun Zhao, Willem Norde, Qipeng Yuan, Fazheng Ren, Yuan Li
PII: S0924-2244(17)30646-5
DOI: 10.1016/j.tifs.2018.06.003
Reference: TIFS 2244

To appear in: Trends in Food Science & Technology

Received Date: 6 November 2017

Revised Date: 1 May 2018
Accepted Date: 4 June 2018

Please cite this article as: Chai, J., Jiang, P., Wang, P., Jiang, Y., Li, D., Bao, W., Liu, B., Liu, B., Zhao,
L., Norde, W., Yuan, Q., Ren, F., Li, Y., The intelligent delivery systems for bioactive compounds in
foods: Physicochemical and physiological conditions, absorption mechanisms, obstacles and responsive
strategies, Trends in Food Science & Technology (2018), doi: 10.1016/j.tifs.2018.06.003.

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1 The intelligent delivery systems for bioactive

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2 compounds in foods: physicochemical and

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3 physiological conditions, absorption mechanisms,

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4 obstacles and responsive strategies

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6 Jingjing Chai 1,2,#, Ping Jiang1,2,#,Pengjie Wang1,Yumeng Jiang1,2,Dan Li1,Weier Bao1,2,Bingxue

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7 Liu1,2,Bin Liu1,Liyun Zhao1, Willem Norde3, Qipeng Yuan2,Fazheng Ren1,Yuan Li 1,*

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8 Beijing Advanced Innovation Center for Food Nutrition and Human Health, Key Laboratory of
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9 Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural

10 University, 100083, China;

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11 College of Life Science and Technology, Beijing University of Chemical Technology, 100029,
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12 Beijing, China;
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13 Laboratory of Physical Chemistry and soft matter, Wageningen University, Dreijenplein 6, 6703

14 HB, Wageningen, The Netherlands

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15 Both authors contributed equally

16 *Corresponding author: yuanli@cau.edu.cn

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17 Tel: +86-10-62738589; Fax: +86-10-62736344

18 Keywords: bioactive compounds, intelligent delivery systems, encapsulation, delivery barriers,

19 bioaccessibility, bioavailability

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20 Abstract

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21 Background: Bioactive natural compounds have received considerable attention due to their

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22 health benefits, including anti-oxidant, anti-cancer, anti-diabetes and cardiovascular

23 disease-preventing functions. However, the stability of these sensitive compounds can be

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influenced by unfavourable environmental conditions during processing and storage. In addition,
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25 delivery of bioactive compounds via the oral route is restricted by various physiological barriers,
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26 including a harsh pH, gastrointestinal (GI) enzymes, the mucus layer and the epithelium.

27 Intelligent delivery systems are promising strategies to protect bioactive molecules from
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28 degradation and improve their bioavailability.

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29 Scope and Approach: We have demonstrated the physicochemical and physiological GI

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30 conditions. The structural composition of the epithelium and transport mechanisms of bioactives

31 and nanoparticles across the intestinal epithelium were discussed. The effects of enhanced
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32 aqueous solubility, stability, bioaccessibility and bioavailability after encapsulation were

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33 illustrated. Furthermore, novel intelligent carriers that are responsive to the oral route, pH,

34 enzymes and cell receptors were also discussed.

35 Key findings and conclusions: This comprehensive multidisciplinary review provides useful

36 guidelines for application of bioactive compounds in food industry. Intelligent carrier systems

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37 are designed to improve the low solubility, poor stability and low bioavailability of bioactive

38 compounds during the processing, storage and oral uptake.

39 Table of contents

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40 Table of contents ............................................................................ Error! Bookmark not defined.
41 Introduction ..................................................................................................................................... 3

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42 1.The structure and function of the GI tract .................................................................................... 6
43 2.The mechanisms of cellular uptake of carriers .......................................................................... 10
44 3. Function and challenges of encapsulation .................................................................................11

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45 4. The intelligent delivery systems for food bioactives ................. Error! Bookmark not defined.
46 4.1 Oral-responsive delivery systems ................................................................................... 15
47 4.2 pH-responsive delivery systems ..................................................................................... 17
48 4.3 Enzymatically-responsive delivery systems ................................................................... 20

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49 4.4 Biorecognition by specific receptors delivery system .................................................... 21
50 4.5 Mucus-penetrating and mucoadhesive delivery systems ................................................ 23
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51 Conclusions and future trends ....................................................................................................... 25
52 Acknowledgement ........................................................................................................................ 25
53 References ..................................................................................................................................... 27
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54

55 Introduction
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56 Food-derived bioactive compounds have gained attention over the past few years due to their

57 potential health benefits in reducing the risks of many diseases, such as diabetes, cancer,
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58 cardiovascular diseases, and obesity (Oh, 2016). These benefits are due to their anti-tumour,

59 anti-inflammatory, anti-oxidative, anti-hypertensive and anti-hyperlipidemic activities, in

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60 addition to their basic nutritional functions. These food-sourced bioactive compounds include
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61 phytochemicals (Velderrain-Rodriguez, et al., 2014), fatty acids (Kruk, Szymanska, Nowicka, &

62 Dluzewska, 2016), vitamins (Katouzian & Jafari, 2016), proteins (Dhaval, Yadav, & Purwar,

63 2016), bioactive peptides (Dhaval, et al., 2016) and bioactive polysaccharides (S. Jiang, Liu,

64 Wang, Xiong, & Sun, 2016). These compounds are often highly sensitive to environmental

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65 stimuli, such as light, heat, low pH and oxygen, during processing and storage (Gleeson, Ryan,

66 & Brayden, 2016). Moreover, problems that occur during oral delivery of bioactive ingredients

67 must be overcome. For example, consumers find that the flavour of some bioactive compounds is

68 unpleasant during direct oral uptake. The poor solubility of hydrophobic compounds greatly

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69 hinders their dissolution in aqueous medium and absorption under gastrointestinal conditions in

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70 the human body. The efficacy of these compounds is decreased by their low stability under

71 processing or storage conditions, such as exposure to heat, light or oxygen. In general, most

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72 bioactive compounds have a low absorption rate through the small intestinal epithelium. Food

73 ingredients may experience digestive degradation under acidic pH conditions and by various

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enzymes (amylase, pepsin, and pancreatin), as well as by mucus barriers overlaying the
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75 epithelium in the gastrointestinal (GI) tract lumen (M. C. Chen, Sonaje, Chen, & Sung, 2011). In

76 addition, food ingredients have limited diffusion across the intestinal mucus and have low
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77 permeability through the intestinal epithelium, greatly impeding their bioavailability. Even if
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78 food ingredients permeate the mucus layer, they may still have low cellular uptake. It has been
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79 reported that the cellular uptake of polyphenols absorbed by carrier-mediated transport is greatly

80 restricted via a “multiple-drug resistance” mechanism. Poly-glycoprotein efflux pumps are

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81 present on epithelial cells and can pump any absorbed polyphenols back to the lumen (Chan,

82 Lowes, & Hirst, 2004).

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83 To overcome these problems, various delivery systems have been developed by masking the
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84 unpleasant taste of the compounds, dissolving hydrophobic compounds into the aqueous phase

85 by incorporating them into hydrophilic microcapsules, providing protection from hazardous

86 environmental conditions and improving permeability through the intestinal mucus and

87 epithelium (Livney, 2010). Various micro/nanocapsules delivery systems can protect bioactive

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88 compounds from degradation in the gastrointestinal (GI) tract. These systems vary in size and

89 structure, which can be used to alter the cargo release kinetics and target delivery to specific

90 sites. Some mucus-penetrating carriers can transport bioactive compounds across the intestinal

91 mucus barriers quickly so that they can significantly absorb into systemic circulation after oral

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92 administration (Lundquist & Artursson, 2016). However, some mucoadhesive biomaterial-based

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93 carriers can extend the residence time of compounds in the intestines and increase their local

94 concentration close to the surface of the epithelial cells (Saura-Calixto, Serrano, & Goni, 2007).

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95 In recent years, food delivery systems have become increasingly functionalized. However, to

96 make carriers more intelligent, responsiveness to the oral cavity, intestinal pH, and enzyme

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conditions, as well as biorecognition under physiological conditions and overcoming the
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98 intestinal mucus barriers, should all be considered when designing an advanced delivery system.

99 Complex coacervation systems are designed for the oral delivery of flavour compounds to
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100 prolong their retention time and increase the sensory perception of foods (Z. Zhang, Zhang, Tong,
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101 Decker, & McClements, 2015). Layer-by-layer carriers are responsive to the intestinal pH, and
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102 they protect encapsulated compounds from degradation and release them to the small intestine

103 (Shi, et al., 2017). Colon-specific carriers can release their encapsulated compounds via
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104 degradation by colonic microorganism enzymes (Kumar, et al., 2017). Receptor-responsive

105 carriers targeted to M cells can greatly improve the cellular uptake of encapsulated compounds
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106 (Tian, et al., 2016). Mucus-penetrating carriers can effectively improve the absorption of their
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107 cargo due to their ability to quickly diffuse through the mucus barriers and arrive at epithelial

108 cells (Y. Li, Arranz, Guri, & Corredig, 2017). By contrast, mucoadhesive carriers may interact

109 with the mucus and achieve a prolonged release of their encapsulated compounds (Sheng, et al.,

110 2015). Thus, intelligent delivery systems have become increasingly important and will provide a

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111 useful platform for facilitating the application of bioactive compounds in the food industry as

112 well as improve their efficacy and bioavailability.

113 Many reviews have been published on the application of bioactive compounds delivery

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114 systems (Ezhilarasi, Karthik, Chhanwal, & Anandharamakrishnan, 2013). However, there is no

115 comprehensive review of natural biopolymer delivery systems that covers all of the aspects of

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116 physicochemical and physiological conditions, absorption mechanisms, obstacles and responsive

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117 strategies in the field. In this review, the physicochemical and physiological conditions and the

118 functions of the GI tract are introduced. The mechanism of digestion and absorption of various

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119 bioactive compounds and nanocarriers is discussed. Last, intelligent delivery of the responsive
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120 delivery systems and mucus-penetrating and mucoadhesive carriers is described and compared.

121 This work provides comprehensive knowledge covering all aspects for designing intelligent
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122 carriers.
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123 1.The structure and function of the GI tract

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124 To design an intelligent delivery system for bioactive compounds in foods, the
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125 physicochemical and physiological conditions of various portions of the human GI tract must be

126 understood. Fig.1 shows various microenvironments at different locations in the GI tract. Oral
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127 delivery technologies can be used to enable nutraceuticals to reach systemic and lymphatic
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128 circulation. Orally administered compounds encounter various barriers in the GI tract before they

129 are absorbed and enter the bloodstream. The oral cavity is the first barrier to bioactive

130 ingredients after ingestion. Typical oral conditions are neutral pH (7.4) with saliva that mainly

131 contains amylase. The oral pH, ionic strength, temperature, flow rate, frictional forces, and

132 salivary enzymes, such as amylases, are responsible for breaking up substances in the oral cavity.

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133 Ingested materials may undergo appreciable changes in composition and structure in the mouth

134 (McClements, 2013). Then, food materials are swallowed in the pharynx and reach the stomach

135 through the oesophagus. The stomach contains pepsin and is a highly acidic environment. Food

136 is physically digested into a thick, semifluid mass called chyme, which is triggered by either

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137 highly acidic gastric fluids (pH 1–2) or multiple digestive enzymes (e.g., proteases, amylases and

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138 lipases). Due to the presence of pepsin, some proteins may be digested into peptides in the

139 stomach. Some gastric tri- and di-acylglycerol degradation by lipase can also occur in the

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140 stomach, leading to the formation of monoacylglycerols and free fatty acids (Arranz, Corredig, &

141 Guri, 2016). In addition, some simple chemical digestion may also occur in the stomach,

142
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allowing chyme to be further digested into macromolecules, such as proteins, fats and
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143 polysaccharides, prior to transfer to the small intestine. Chyme moves to the duodenum and

144 ileum and is digested by pancreatic enzymes (proteases, lipases, and amylases) and other
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145 digestive enzymes in the small intestine. The intestinal pH changes to 6.0-7.0. Here, the majority
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146 of tri- and di-acylglycerols are degraded into free fatty acids and monoacylglycerols by lipase.
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147 Starch is degraded into oligosaccharides and glucose by amylases, and proteins are degraded into

148 peptides and amino acids by proteases for further absorption by epithelial cells (McClements,
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149 2013). However, nutrients permeate the mucus layer and arrive at epithelial cells for absorption.

150 Although the nutrients can pass through mucus barriers, they encounter efflux pump
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151 polyglycoproteins on the epithelial cell surface that pump them back into the lumen via a
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152 “Multiple-Drug Resistance” mechanism. Although ingested food materials are mostly degraded

153 and absorbed by the stomach and small intestine, some components, such as dietary fibre, are

154 non-digestible due to their special composition and structure. These components pass to the

155 colon, where the pH is 7.0-8.0, and are disintegrated there by diverse microbes (Arranz, et al.,

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156 2016). For example, dietary fibre is converted to short-chain fatty acids and other products by

157 microbial enzymes, such as dextranase, which may be beneficial to human health.

158 Absorption of food ingredients and nutraceuticals mainly occurs in the small intestine. The

159 intestinal epithelium is a crucial physical and physiological barrier that affects absorption, and it

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160 includes two-part of mucus barrier and cell layers (Fig.2). The physical structure of the mucus

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161 layer is similar to a hydrogel with highly branched polysaccharides and negatively charged

162 glycoproteins, i.e., mucin, which is highly viscoelastic and adhesive. The mucus hydrogel has an

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163 average pore size of hundreds of nanometres. Food ingredients must permeate through the mucus

164 barriers and arrive at the enterocyte surface for further absorption. However, diffusion of food

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ingredients can be greatly hindered when passing through the mucus due to hydrogen bonding,
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166 electrostatic, hydrophobic interactions, as well as polymer entanglement between components

167 and mucus polymers. Therefore, small hydrophilic ingredients, such as vitamin B and
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168 oligosaccharides, can easily diffuse through the barrier. Hydrophobic ingredients such as
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169 β-carotene can interact with the mucus via hydrophobic interactions, hindering their diffusion to
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170 the cell layer. Positively charged compounds, such as bioactive peptides, may adhere to the

171 mucus polymers via electrostatic attractions. Besides, the compounds larger than the mucus pore
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172 size will not easily pass through the mucus network (Boegh, Baldursdottir, Mullertz, & Nielsen,

173 2014; Yu, Wang, et al., 2016). The cell layer consists of enterocytes, goblet cells and
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174 membranous/microfold (M) cells. Enterocytes, the most abundant cells in the small intestine,
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175 have microvilli on the lumen side and absorb nutrients via active transport or passive diffusion.

176 Goblet cells, scattered among intestinal cells, can secrete mucus, which is a semipermeable

177 barrier that can exchange components but can prevent the permeation of most bacteria and

178 pathogens (Cone, 2009; Ensign, Cone, & Hanes, 2012; Pereira De Sousa, et al., 2015). M cells,

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179 distributed in Peyer’s patches, possess more mitochondria but fewer lysosomes than enterocytes

180 and do not have a mucous glycocalyx covering their surface (Begue, et al., 2006; Gullberg, et al.,

181 2006; Tyrer, Foxwell, Cripps, Apicella, & Kyd, 2006). M cells have high transcytotic capacity,

182 are antigen-specific, and participate in immune responses due to their special structure. Fig.2 also

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183 shows four transport mechanisms for food ingredients passing through the small intestinal

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184 epithelial cell layer: (1) Passive diffusion, which is an energy-independent pathway due to

185 osmotic pressure and occurs through either paracellular or transcellular routes. Transcellular

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186 diffusion is a process by which small hydrophobic molecules fuse to the cellular membrane and

187 are then transferred to the membrane, while paracellular diffusion occurs when small hydrophilic

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molecules are transported through the junctions between intestinal epithelium cells (Burton,
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189 Conradi, & Hilgers, 1991). (2) Receptor-mediated transport, wherein bioactives specifically bind

190 to the cell-surface receptor and are internalized by cells (Swaan, 1998). The absorption of
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191 vitamin B12 (Seetharam, 1999), insulin (Swaan, 1998), and transferrin (Berry, Charles, Wells,
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192 Dalby, & Curtis, 2004), among others are all receptor-mediated transport pathways. (3)
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193 Carrier-mediated transport allows food compounds to enter or be expelled from cells due to an

194 osmotic pressure gradient utilizing the cellular protein transporters. These transporters include
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195 energy-dependent active transport and facilitated diffusion (Pawar, et al., 2014). For example,

196 the absorption of glucose and minerals, such as Na+, K+, Ca2+, occurs via carrier-mediated
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197 transport. (4) Efflux pump mechanism, for which p-glycoprotein (P-gp) is the most important
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198 ATP-dependent efflux pump in the intestinal epithelium. Bioactive compounds can be pumped

199 out from enterocytes by P-gp via a “multi-drug resistance” mechanism, leading to limited

200 bioavailability. It has been reported that the low bioavailability of polyphenols is primarily

201 caused by this mechanism (Z. Liu & Hut, 2007).

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202 2.The mechanisms of cellular uptake of carriers

203 In general, the absorption of most bioactive compounds through the epithelium is not highly

204 efficient. For example, hydrophobic compounds are mostly absorbed by simple passive diffusion.

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205 VA is absorbed via bile salt micelle transport. Polyphenols are absorbed via carrier-mediated

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206 transport, but the efflux pump P-gp exists on epithelial cells and can pump absorbed polyphenols

207 back to the lumen, greatly restricting their cellular uptake. Therefore, delivery carriers must be

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208 applied to overcome the low absorption rate of bioactive compounds due to the limited cellular

209 uptake. Their uptake can be improved by carrier delivery. Carriers can be designed to deeply

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penetrate the mucus layer and improve transmembrane permeability through epithelial cells. In
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211 addition, carriers can transport a large amount of ingredients in one cargo package and actively

212 enter cells. Moreover, carriers can overcome the influence of efflux pumps. Cellular uptake of
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213 carriers and bioactive compounds differs and it is a prerequisite for understanding the
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214 mechanisms of the cellular uptake of carriers before their designing and application. Passive
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215 transcellular transport of nanoparticles (NPs) occurs through nonspecific permeability pathways,

216 which are very limited due to the large size of NPs (Ramesan & Sharma, 2009). NPs can also be
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217 transported through active transport via energy-dependent mechanisms, which is more efficient

218 than passive transport (M. C. Chen, et al., 2011). Active transcellular transport has been
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219 categorized into four different mechanisms: phagocytosis, macropinocytosis, clathrin-mediated

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220 endocytosis and caveolin-mediated endocytosis (Fig.3). The phagocytosis endocytosis pathways

221 are more likely to occur in M cells. Caveolin-dependent endocytosis, clathrin-dependent

222 endocytosis and/or micropinocytosis are the main pathways for NP uptake in enterocytes, which

223 is very complex and occurs via multiple routes, giving rise to an active demand for novel NPs to

224 enable and promote transcytosis (Yu, Yang, Zhu, Guo, & Gan, 2016). For instance,

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225 curcumin-loaded soybean Bowman−Birk inhibitor NPs (C. Liu, Cheng, & Yang, 2017) are

226 mainly found in the clathrin-mediated endocytosis pathway. The honokiol-loaded amphiphilic

227 codendrimer porous graphitized carbon (PGC) NPs mainly occur via caveolae- and

228 clathrin-mediated endocytosis (Guo, et al., 2017). In general, enterocytes can only absorb NPs

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229 smaller than 100 nm, while M cells of Peyer's patches tend to take up NPs larger than 500 nm (M.

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230 Chen, et al., 2013).

231 Although hydrophilic bioactive compounds preferably transport through the paracellular

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232 pathway, the presence of tight junctions (TJs) between cells leads to a very small intercellular

233 space of approximately 1 nm, greatly limiting their diffusion. TJs are important barriers of

234
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permeation between cells, especially for high-molecular-weight compounds (Ramesan &
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235 Sharma, 2009). To speed their paracellular transport, opening TJs is an effective strategy.

236 N-trimethyl chitosan chloride (TMC) conjugated NPs have been shown to effectively open TJs
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237 reversibly and improve oral absorption of insulin (Sheng, et al., 2015).
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238 3. Function and challenges of encapsulation

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239 The unpleasant flavour, poor water solubility and chemical instability in vivo are the main

240 causes of the low bioavailability of nutraceuticals and drugs since they must pass through many
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241 barriers before being absorbed by the human body. Therefore, it is essential to develop a strategy
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242 to overcome these problems (Z. Li, Jiang, Xu, & Gu, 2015). Encapsulation has been shown to be
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243 an effective method to mask the unfavourable taste as well as improve the solubility and stability

244 of functional ingredients via the oral route. Encapsulation technology has been applied in the

245 food sector to maintain good quality and characteristics, such as aqueous solubility, texture,

246 taste, colouring strength, and stability, during processing and storage. Because the absorption

247 rate of bioactive compounds is closely correlated to their aqueous solubility, most bioactive

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248 compounds are hydrophobic and thus have a low absorption rate in the GI tract. The

249 “micelle”-like structure with a hydrophobic core and hydrophilic corona allow their

250 incorporation of hydrophobic bioactive compounds (such as curcumin and fat-soluble vitamins)

251 inside the core. The hydrophobic ingredients loaded carriers possessed a good colloidal stability

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252 due to hydration and surface charge repulsion (Huang, Yu, & Ru, 2010). In this way, the aqueous

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253 solubility and absorption of hydrophobic compounds can be significantly enhanced. Many carrier

254 systems have been applied to increase the solubility of hydrophobic compounds; for example,

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255 procyanidin can be successfully encapsulated into zein nanoparticles, which significantly

256 increases the solubility of procyanidin in aqueous systems (Zou, Li, Percival, Bonard, & Gu,

257
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2012). When vitamin D (VD) is encapsulated in β-lactoglobulin by molecular self-assembly and
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258 co-assembly, the solubility of this vitamin is dramatically enhanced (Gorska, Szulc,

259 Ostrowska-Ligeza, & Wirkowska, 2012). The solubility of linoleic acid-encapsulated

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260 β-lactoglobulin nanocapsules was enhanced from 12% to 45% (Gorska, et al., 2012), and the
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261 aqueous solubility of CoQ10 encapsulated in albumin nanoparticles was significantly enhanced
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262 (Matsushita, Oshima, Takahashi, & Baba, 2013). Some bioactive ingredients, such as vitamins

263 and unsaturated fatty acids, are not stable when exposed to light, oxygen and heat. Encapsulation
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264 techniques have been used by the food industry to encapsulate, protect, and release a wide range

265 of bioactive components. Researchers have successfully encapsulated vitamin E (VE) into
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266 modified tapioca starch nanocapsules. In this way, the stability of VE is dramatically enhanced.
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267 After 60 days of storage at 4-35°C, the retention of VE was approximately 50% of its initial

268 value, and good solubility was maintained (Hategekirnana, Masamba, Ma, & Zhong, 2015).

269 Amphiphilic peptides were obtained after hydrolysis of caseins, which can co-assemble into

270 micellar nanoparticles. VD can be incorporated into hydrophobic cores via hydrophobic

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271 interactions, which significantly improves its thermal stability (Haham, et al., 2012). Vitamin C

272 (Vc) is also unstable when exposed to light, oxygen and heat (Bendich, Machlin, Scandurra,

273 Burton, & Wayner, 1986). The inorganic layer SiO2 shell-encapsulated Vc was above 95%, while

274 the non-encapsulated Vc was below 10% after 4 weeks (Yang, Lee, Han, Park, & Choy, 2003). In

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275 addition, formation of nanocomplexes can improve the stability of unsaturated fatty acids.

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276 Nanocapsules formed by pectin and β-lactoglobulin protect DHA from degradation: only

277 approximately 5–10% loss occurred over 100 h at 40°C compared to 80% loss for

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278 nonencapsulated DHA (Zimet & Livney, 2009).

279 Carrier systems can improve the solubility and stability of bioactive compounds as mentioned

280
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above, but challenges must still be overcome to deliver food ingredients via the oral route, such
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281 as the pH, ionic strength, enzymes and mucus barriers in the GI tract. These challenges will

282 greatly affect properties of carriers, consequently influencing the bioavailability of bioactive
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283 compounds. The current design of food carriers emphasizes the bioaccessibility rather than the
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284 bioavailability of encapsulated compounds. Bioaccessibility is the fraction of ingredients

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285 released from a food substrate to the GI lumen, which facilitates intestinal absorption

286 (Saura-Calixto, et al., 2007). Bioavailability is an accurate indication of the efficient utilization
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287 of bioactive compounds that are actually absorbed by intestinal enterocytes and move into blood

288 circulation. The study of bioaccessibility is focused on digestion in vitro, whereas bioavailability
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289 is related to absorption in vivo. To improve the oral bioavailability of food ingredients, more
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290 intelligent carrier systems should be developed for on-demand delivery and release of bioactive

291 compounds at the right time and right place. These more effective carriers should be designed to

292 improve the retention capability, intestinal pH-responsive properties, mucus permeation, and

293 cellular uptake of bioactive compounds.

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294 4. The intelligent delivery systems for food bioactives

295 Currently, there is an increasing demand for intelligent delivery systems for encapsulated

296 compounds that are only released at the appropriate time and place in a controlled release

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297 manner with targeted site-specific delivery. Simultaneously, oral bioavailability can be

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298 effectively enhanced by carriers with a higher mucus-penetrating ability and high epithelium

299 cellular uptake rate (Ezhilarasi, et al., 2013). According to previously described

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300 microenvironments for various portions of the GI tract (Fig.1), intelligent carriers can be

301 designed to be responsive to environmental changes in the GI tract, which contains the mouth,

302
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stomach, small intestine, and colon (Table 1). We categorized intelligent food delivery systems
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303 into oral-responsive, pH-responsive, enzyme-responsive, targeted-delivery, mucus-penetrating

304 and mucoadhesive carriers, according to their specialty (Fig.4). First, flavour compounds can
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305 undergo controlled release in the mouth by a complex coacervation system to prolong their
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306 retention time and increase the sensory perception of the foods (Z. Zhang, Zhang, Decker, &
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307 McClements, 2015). The carriers are responsive to the intestinal pH to protect the encapsulated

308 compounds in the stomach and release them in the small intestine after the carriers are ruptured
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309 by the intestinal conditions (Garinot, et al., 2007). Colon-specific carriers are designed to release

310 their encapsulated compounds when their structure is degraded by colonic microorganism
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311 enzymes, such as dextranase (Garinot, et al., 2007). Cellular uptake can be greatly improved for
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312 ligand-conjugated carriers via receptor-mediated endocytosis mechanisms (T. Jiang, et al., 2014).

313 Compared with free compounds, mucus-penetrating carriers can quickly diffuse through mucus

314 barriers and arrive at epithelial cells at a higher concentration for improved absorption of the

315 encapsulated compounds (Y. Li, et al., 2017). By contrast, mucoadhesive carriers can be retained

316 in the mucus for a long time and release encapsulated compounds over a prolonged period

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317 (Sheng, et al., 2015). Each type of carrier will be discussed in detail in the following section.

318 4.1 Oral-responsive delivery systems

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319 Flavour compounds are often volatile sensitive molecules, such as aldehydes, ketones, and

320 other phytochemicals (Wu, Shen, Larcinese Hafner, Erni, & Ouali, 2016). Delivery technology

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321 has been widely used in flavour encapsulation to enhance certain favourable flavours and mask

322 some unpleasant flavours. The problem encountered by food flavour compounds is that they are

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323 too volatile to be retained in foods over a long period. Their flavour concentration may be

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324 reduced due to early release during storage. The main purpose of encapsulation is to embed
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325 bioactive agents into specific delivery systems to decrease evaporation and enhance their

326 solubility and chemical stability during storage. At the same time, carriers can release bioactive
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327 agents at the appropriate site of action, such as the mouth (McClements, 2017). Carrier systems

328 have been proposed to encapsulate flavour compounds in food products and have demonstrated
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329 responsive and sustained release under oral conditions. For instance, aroma menthone and
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330 menthol can be encapsulated into the amylose α-helix via hydrogen bonding to form

331 starch/flavour complexes that are responsive to saliva amylase. The flavour can be well-retained
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332 under storage conditions before oral uptake and can be released slowly in the oral cavity during
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333 uptake. Simulated saliva fluid release studies indicated that the aroma underwent sustained
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334 released from the complexes and remained longer in the oral cavity because starch was gradually

335 hydrolysed by saliva α-amylase (Ades, Kesselman, Ungar, & Shimoni, 2012). A starch Pickering

336 emulsion has been fabricated to encapsulate curcumin, and it increased its storage stability

337 against heat and oxygen. The starch Pickering emulsion is susceptible to α-amylase in simulated

338 saliva fluid, leading to an early release of encapsulated curcumin (M. S. Wang, Chaudhari, Pan,

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339 Young, & Nitin, 2014). Whey protein isolate (WPI) − pectin stabilized multilayer emulsions are

340 used as a vehicle to deliver volatile flavour compounds in the oral cavity. Under oral conditions,

341 the release of hydrophobic volatiles, such as pentanone, ethyl butyrate and heptanone, was

342 triggered. The interaction between pectin and WPI was weakened due to repulsion between

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343 negatively charged WPI and pectin at pH 7 (Benjamin, Silcock, Beauchamp, Buettner, &

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344 Everett, 2013). McClements et al. encapsulated lipophilic active ingredients using a

345 casein/alginate complex coacervation hydrogel. Food-grade delivery systems can effectively

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346 protect lipid droplets during storage but release them in the mouth due to the dissociation of

347 hydrogel particles at pH 7 (Z. Zhang, Zhang, Decker, et al., 2015). The authors also found that

348
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hydrogel particles composed of gelatine and caseinate can encapsulate polyunsaturated lipids to
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349 guard against oxidation during storage, but are released in the mouth via melting of gelatine at

350 body temperature (Z. Zhang, Zhang, Tong, et al., 2015). People can feel the roughness of the
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351 particles when their size larger than 10 µm. It is important to control the size of the oral delivery
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352 carriers below 10 µm. Besides, the interaction between the carriers and the tongue mucus layer
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353 should be taken into consideration.

354 On the other side, oral delivery systems are also used for masking unfavourable flavour in
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355 foods. For example, Jaleh et al. has fabricated lipid nanocapsules coated with carbohydrate
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356 biopolymers (chitosan, alginate, and low methoxypectin) containing hesperetin. Their sensory
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357 analysis demonstrated that the developed nanocapsules significantly masked the bitterness of

358 hesperetin (Fathi & Varshosaz, 2013). Phenobarbital loaded carriers based on microemulsions

359 (MEs) for oral administrations could also attenuate the phenobarbital bitter taste (Monteagudo, et

360 al., 2014). Microcapsules prepared by gelatin and SPI complexes via spray drying was used for

361 diminishing the bitterness of casein hydrolysate (Favaro-Trindade, Santana, Monterrey-Quintero,

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362 Trindade, & Netto, 2010). Besides, to mask the strong garlic flavour, β-lactoglobulin

363 microcapsules were developed to encapsulate the thiosulfinate allicin (Wilde, Keppler, Palani, &

364 Schwarz, 2016). In addition, oral delivery systems are also applied for studying oral processing

365 and sensory perception. For example, the vanillin-loaded starch nanoparticles prepared by

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366 electrospray method were used to study the taste perception of vanillin after consumption. Their

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367 results indicated that the starch NPs strengthened the flavour perception of vanillin in the mouth

368 due to gradually degradation by the saliva amylase in oral cavity (Ege, et al., 2017). The delivery

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369 systems based on carboxymethyl cellulose could give rise to a controlled release and taste

370 perception of sodium in the oral cavity, resulting in a flavour balance of sodium (Aditya,

371 Espinosa, & Norton, 2017).

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372 4.2 pH-responsive delivery systems
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373 A variety of proteins, peptides, polyphenols, vitamins and probiotics are easily degraded in
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374 highly acidic environments that contain many digestive enzymes, such as pepsin in the GI tract.
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375 These conditions cause great losses before the compounds reaching the small intestine. With

376 proper encapsulation, these compounds can be protected against degradation by acids and
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377 enzymes in the stomach (Ezhilarasi, et al., 2013). The encapsulated compounds are retained in
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378 the stomach but released in the small intestine, which is essential to increase their
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379 bioaccessibility. Therefore, functional microcapsules should possess responsiveness to the

380 intestinal neutral pH and avoid early release and decomposition under acidic enzymatic stomach

381 conditions, which is favourable for intestine-specific release.

382 The pH-responsive delivery system has been well explored in the literature. Complex

383 coacervation with WPI/gum Arabic (GA) was used to deliver live probiotics (L. paracasein E6

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384 and L. paraplantarum B1), which can retain their viability to a great extent compared to free cells

385 in a simulated gastric juice. Cells were tuned for release at pH 7.0 due to the switching of

386 attraction to repulsion between WPI and GA (Bosnea, Moschakis, & Biliaderis, 2014). The

387 drawback of the pH responsive coacervates capsules is their instability under high physiological

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388 salt concentration around 150 mM. The oppositely charged polymers may dissociate under such

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389 a high salt concentration due to the charge screening effect. Cross-linking between the oppositely

390 charged polymers may solve this problem. β-carotene-encapsulated Fe3+-crosslinked oxidized

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391 starch microspheres were able to maintain a stable structure in simulated gastric fluid (pH < 2)

392 and effectively improve the release of bioactive substances in simulated intestinal fluid (pH 7.0)

393
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(S. Wang, Chen, Lang, et al., 2015). Similar pH-responsive effects were also observed in
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394 β-carotene nanoemulsion-absorbed starch hydrogels (S. Wang, Chen, Shi, et al., 2015). Chitosan

395 (CS)-coated oxidized Konjac glucomannan (OKGM) microspheres, in which β-carotene and
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396 anthocyanins can be simultaneously incorporated, possess intestinal pH responsiveness (Fig.4)

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397 (Shi, et al., 2017). They were stable under acidic stomach conditions (pH < 2) and can rupture to
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398 release loaded antioxidants specifically under neutral intestinal conditions (pH 7.0), achieving

399 the goal of intestine-specific release. Moreover, dual bioactives can be loaded into CS-OKGM
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400 microspheres, which endowed the microspheres with synergistic antioxidant activity and

401 enhanced their heat stability. A similar responsiveness was also found for double-networking
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402 microspheres of Fe3+-cross-linked oxidized polysaccharides/glutaraldehyde cross-linked chitosan

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403 oligosaccharides (Lu, et al., 2015). The disadvantages of cross-linked polymers hydrogels are

404 that they usually absorb large amount of water which is unfavourable during the food processing.

405 Due to strong hydrogen bonds and hydrophobic interactions between polyphenols and human

406 serum albumin (HSA), the stability of polyphenol under neutral and slightly alkaline pH

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407 conditions was significantly enhanced after encapsulation in HAS (Zheng Li, et al., 2015).

408 (-)-Epigallocatechin-3-gallate (EGCG) is an important antioxidant from tea extracts, but its

409 stability and solubility are rather limited; thus, it is important to stabilize and deliver EGCG by

410 encapsulation. Using an emulsion solvent diffusion method, encapsulated EGCG becomes stable

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411 under stomach acidic conditions of pH 1.2 and under rat small intestinal conditions. Moreover,

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412 encapsulated EGCG was released at intestinal pH and remained stable at stomach pH (Onoue,

413 Ochi, & Yamada, 2011). The ability of probiotics to survive in the GI tract of the host strongly

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414 influences their function. Large amounts of probiotics should be stable through the digestive

415 tract. However, the strong acid and bile salts in the stomach result in a low survival rate for

416
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bacteria. Various delivery systems that have been developed for the encapsulation of probiotics
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417 have been shown to increase their viability (W. Liu, Chen, Cheng, & Selornulya, 2016). For

418 example, a novel intestine-specific carrier consisting of a Ca2+-alginate/protamine composite

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419 shell and a Lactobacillus casein-encapsulated Ca2+-alginate core was successfully developed by
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420 Mei et al. The results showed that encapsulated Lactobacillus casein was efficiently protected in
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421 the stomach but was rapidly released in the small intestine due to rapid degradation of the

422 core-shell structure (Mei, et al., 2014). A hydrogel microsphere based on an

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423 ethylenediaminetetraacetic acid-calcium-alginate (EDTA-Ca2+-Alg) system was successfully

424 fabricated as a pH-responsive oral delivery carrier for Lactobacillus rhamnosus ATCC 53103.
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425 This system was able to protect the probiotic from the acidic stomach conditions but was
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426 gradually released in the intestine, where the gel structure collapsed at pH 7.0–8.0 (Zheng, et al.,

427 2017).

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428 4.3 Enzymatically-responsive delivery systems

429 Various enzymes, such as dextranases, β-mannanase are secreted from the colonic

430 microflora present along the GI tract. Therefore, the design of colonic enzymes-responsive

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431 microcapsules is promising for colon-specific delivery systems (Perez-Esteve, Ruiz-Rico,

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432 Martinez-Manez, & Manuel Barat, 2015). Konjac glucomannans (KGM) were commonly used

433 food polysaccharides in colon-specific delivery. For example, the KGM–hydroxypropyl

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434 methylcellulose capsules were reported to deliver 5-aminosalicylic acid specifically to colon

435 because it can avoid the degradation of gastric juice but released at colon due to the degradation

436
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of colonic β-mannanase (C. Zhang, Chen, & Yang, 2014). The carrier system based on KGM and
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437 xanthan gum (XG) mixture was degraded by β-mannanase at colon instead of small intestine,

438 having a sustained release properties for embedding compounds (Alvarez-Mancenido, 2008). A
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439 dextran hydrogel loaded with bioactive compounds were stable under physiological conditions in
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440 the GI tract and only released specifically in the colon due to the degradation by colonic
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441 microbial dextranases (Hovgaard & Brondsted, 1995). Hydrogels composed of poly acrylic acids

442 (PAA) and glycidyl methacrylate dextran (GMD) also showed a dextranase responsive property.
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443 Entrapped 5-aminosalicylic acid displayed insignificant release under both gastric and intestinal

444 pH conditions but was quickly released from the PAA/GMD hydrogel due to the hydrolysis of
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445 glycosidic bonds by colonic dextranase (Kim & Oh, 2005). Chitosan coated liposomes
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446 (chitosomes) were designed to have a pancreatic lipase responsive release of encapsulated

447 carotenoids. Chitosan layer controlled the permeability of the lipase approaching to the

448 liposomes in small intestine, providing a sustained release character (Tan, Feng, Zhang, Xia, &

449 Xia, 2016). Interestingly, the kinetics of lipid digestion can be tuned by carrier systems due to

450 the controlled accessibility of the degestive lipase to oil encapsulated, which can be used to

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451 design low-calorie foods. For example, Zeeb et al. found that lipid digestion could be tuned by

452 modifying the numbers of layers of microcapsules coated on oil droplets. The colloidal stability

453 of double-layer O/W emulsions was improved, facilitating the permeation of lipase through the

454 layer and changing encapsulated lipid into free fatty acids and monoacylglycerols. However, in a

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455 primary single layer emulsion, flocculation or coalescence occurred after exposure to gastric

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456 conditions, leading to a slower rate of oil digestion in the small intestine due to the decreased

457 exposed surface area. It seems smaller and stable emulsion droplets have a faster digestion rate

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458 (Zeeb, Weiss, & McClements, 2015). The limitations of the intestinal-enzymatic responsive

459 carriers are their wall materials which are quite restricted to some intestinal amylase specific and

460
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colonic microbial enzymes cleavable polysaccharides. Protein alone may be not suitable for such
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461 application since they are already hydrolysed in stomach.
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462 4.4 Biorecognition by specific receptors delivery system

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463 The coupling of a targeting molecule, such as peptide ligands, at the surface of carriers
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464 facilitates its interaction with surface receptors on the targeted tissue. This is an efficient method

465 to improve the cellular uptake of bioactive compounds especially some immune-regulating
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466 compounds (Yun, Cho, & Park, 2013). The CKSTHPLSC (CKS9) peptide, as a novel M
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467 cell-homing peptide ligand, has been conjugated to chitosan nanoparticles and has served as an
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468 efficient oral carrier that could target the follicle-associated epithelium region of Peyer’s patches.

469 The binding affinity and transcytotic property of the CKS9 peptide to M cells were significantly

470 enhanced, and in vivo specific localization to the follicle associated epithelium (FAE) of Peyer’s

471 patches was achieved (Yoo, et al., 2010). CSKSSDYQC (CSK)-modified solid lipid

472 nanoparticles (SLNs), as potential carriers for hydrophobic drug transport, such as atorvastatin

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473 calcium (ATC), were prepared by coupling the peptide ligand CSK to stearic acid. This CSK

474 peptide-modified SLN exhibited a strong mucus-penetrating ability across the intestinal cell

475 monolayer and prominently increased the ATC bioavailability (Tian, et al., 2016). Another

476 peptide ligand, RGD (Arg-Gly-Asp), was covalently linked on antigen-loaded PEGylated

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477 PLGA-based nanoparticles to target human M cells. The RGD-labelled nanoparticles

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478 significantly increased penetration of compounds into the human follicle-associated epithelium

479 (co-cultures) due to the interactions between the RGD ligand and β1 integrin on the apical

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480 surface of the co-cultures. In vivo studies further indicated that RGD-labelled nanoparticles could

481 be particularly concentrated in M cells (Garinot, et al., 2007). A targeting NP was prepared by

482
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coating coumarin 6-loaded poly (ethylene glycol)-block-poly (ε-caprolactone) (PEG-b-PCL)
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483 micelle cores with a transferrin receptor (TfR)-specific 7peptide (7pep, Histidine-

484 Alanine-Isoleucine-Tyrosine- Proline-Arginine-Histidine, HAIYPRH) (Du, et al., 2013). The

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485 developed NP possessed significantly increased cellular uptake and entered cells through a
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486 specific clathrin-mediated mechanism related to a receptor-mediated mechanism. Furthermore,

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487 the FQS peptide (FQSIYPpIK), a highly conserved receptor expressed on the intestinal

488 epithelium, can specifically bind to the integrin avb3 receptor. The conjugation of FQS-TMC to
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489 insulin-loaded NPs formed by poly (lactide-co-glycolide)–monomethoxy-poly (polyethylene

490 glycol) (PLGA–mPEG) enabled higher cellular uptake and enhanced ability for decreasing the
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491 blood glucose level (C. Liu, et al., 2016). These targeted delivery systems are commonly used in
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492 pharmaceuticals but limited in use in food application. Safe and green approaches such as

493 enzymatically modification for conjugating those ligands on the carriers should be considered in

494 food application.

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495 4.5 Mucus-penetrating and mucoadhesive delivery systems

496 A mucus layer is a barrier not only for bioactive compound absorption but also for carrier

497 transport. Foreign particles are trapped by mucus layers due to steric hindrance or adhesion and

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498 are removed by the mucus within the range of seconds to several hours up to the anatomical site

499 (S. Duennhaupt, Kammona, Waldner, Kiparissides, & Bernkop-Schnuerch, 2015). It has been

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500 shown that liposomes containing EGCG exhibited stronger interactions with human intestinal

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501 mucus than liposomes containing β-carotene because hydrophobic bioactive molecules affect the

502 rheological properties of the mucus layer, but hydrophilic bioactive molecules do not. Caco-2

503
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(no mucus) and Caco-2/HT29-MTX (mucus-secreting cells) co-culture models were used to
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504 study mucus-liposome interactions (Y. Li, et al., 2017).
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505 In recent years, “mucus-penetrating particle” (MPP) (Lai, Wang, & Hanes, 2009) systems

506 have offered the possibility for carriers to efficiently penetrate the mucus layers and reach the
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507 absorption membrane as deeply as possible, as these carriers can quickly transport across the
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508 epithelium and reach systemic circulation. One strategy is to design NPs with reduced

509 interactions with mucus by decorating their surface with hydrophilic and electrically neutral
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510 Polyethylene glycol (PEG). PEG, as a widely used hydrophilic polymer, is frequently used to

511 coat NPs to improve their mucus penetration ability. For instance, Li et al. have examined the
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512 influence of the chain length (500–5000) of PEG-modifying micelles on membrane permeability
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513 and oral bioavailability for delivering trans-retinoic acid (ATRA). Their results indicated that a

514 1000 PEG chain length of ATRA-PEG micelles endowed them with better oral bioavailability

515 (Zhenbao Li, et al., 2015). A nanostructured lipid carrier decorated with a dextran–protamine

516 (Dex–Prot) complex may provide a charge-neutral surface, allowing easy penetration through the

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517 intestinal mucus layer (Lai, et al., 2009). Furthermore, the mucus permeability of various

518 polymers, such as dextran (DEX), aminodextran (ADEX), cyclodextrin (HPBCD),

519 mannose-amine (MA) and PEG-modified NPs, were compared. The results showed that NPs

520 coated with MA presented the best permeability through a mucus layer (Iglesias, et al., 2017).

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521 Furthermore, more consideration should be taken for designing carriers to further overcome the

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522 intracellular degradation by lysosomal enzymes. Some protease enzymes present in endosomes

523 can initiate protein degradation, further leading to the complete degradation of carriers and the

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524 tracking of the bioactive ingredients inside of lysosomes. The carriers should be designed to

525 escape from the lysosome thus can further deliver them into the cytoplasm and later enter into

526 blood circulation.

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527 The mucoadhesive delivery system is an oral delivery strategy that is mainly used for poorly
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528 absorbed ingredients. This system aims to extend the retention time and accumulation on the

529 mucosa and release cargo in close proximity to the absorption site (Sarah Duennhaupt, et al.,
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530 2011). Thiolated polymers, such as thiol groups, conjugated poly(acrylates), chitosan or
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531 deacetylated gellan gum derivatives, can interact with cysteine-rich subdomains of mucus

532 glycoproteins via disulphide bonds to improve their mucoadhesion (Leitner, Walker, &
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533 Bernkop-Schnurch, 2003). Palazzo et al. compared the mucoadhesive properties of poly(isobutyl
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534 cyanoacrylate) (PIBCA) NPs coated with low-molecular-weight (LMW) chitosan (CS) and
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535 glycol chitosan (GCS) modified with N-acetyl cysteine (NAC) and reduced glutathione (GSH)

536 (Palazzo, Trapani, Ponchel, Trapani, & Vauthier, 2017). They found that PIBCA NPs coated

537 with GCS-GSH presented the best mucoadhesive performance. In addition, solid lipid

538 nanoparticles coated with a chitosan polymer have been shown to significantly improve the oral

539 bioavailability of curcumin (Ramalingam, Yoo, & Ko, 2016). Mucoadhesive chitosan-coated

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540 porous silicon nanocarriers were prepared for dual peptide release (glucagon-like peptide-1 and a

541 dipeptidyl peptidase-4 (DPP4)). Co-loaded nanocarriers are expected to release their

542 encapsulated peptides with enhanced mucoadhesion due to chitosan surface modification

543 (Shrestha, et al., 2015). N-trimethyl chitosan chloride (TMC) is another biocompatible polymer

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544 with mucoadhesive properties that has been used to modify nanocarriers to improve their

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545 mucoadhesive ability. For example, polylactide-co-glycoside (PLGA) NPs coated with TMC

546 (TMC-PLGA NPs) were prepared for oral insulin delivery. After oral administration in mice, the

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547 TMC-PLGA NPs could not only protect insulin from enzymatic degradation in the GI tract but

548 also prolong its residence time at the absorption site due to the mucoadhesive property of TMC

549
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(Sheng, et al., 2015). The strategies of avoiding the adhesion between the stomach mucus and the
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550 intestinal specific carriers should be taken into consideration.
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551 Conclusions and future trends

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552 The low stability and off-target effect of bioactive compounds under physiological
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553 conditions (pH, enzymes, and intestinal mucus barrier) in the GI tract lead to low bioaccessibility
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554 and bioavailability. Various obstacles may hinder active compounds-loaded nanocarriers from

555 reaching the target site due to the complicated physiological environment of the human body.
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556 Therefore, smart delivery systems are needed to protect and transport bioactive compounds to the
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557 specific target sites where they needed. Intelligent carriers that are responsive to GI conditions

558 can be designed to specifically release compounds into the intestine according to the neutral pH,

559 microbial enzymes, specific receptors and mucus barriers of the epithelial cells. Most

560 importantly, bioactive compounds can be specifically delivered to the intestine for further

561 absorption and utilization. Currently, most researchers are interested in studying the stability of

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562 these compounds against the harsh environment under simulated GI conditions while

563 overlooking the actual stability and bioavailability in vivo. However, more realistic models

564 should be developed given the mucus barriers, cellular uptake, transport mechanisms and

565 metabolism to accurately evaluate the stability and bioavailability of bioactive compounds after

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566 encapsulation. New materials composed of natural biopolymers, such as polysaccharides,

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567 proteins and even lipids, should be explored for preparing novel capsules. In smart designs with

568 high loading capacities, the compound stability in the GI tract, easy penetration through the

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569 intestinal mucus layers, enhancement of cellular uptake and opening of the cellular junctions

570 should be fully considered. Besides, multifunctional nanocarriers based on hydrogel or

571
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self-assembled NPs that are simultaneously responsive to physiological conditions (pH,
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572 enzymes, and intestinal mucus barrier) in the GI tract are promising research directions. The

573 delivery systems of nanoscale can effectively enhance the sensory perception, stability and
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574 bioavailability should be also explored. The in vivo toxicity of these delivery systems should be
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575 investigated in terms of cell viability, biodistribution and metabolism. The information addressed
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576 in this review may be helpful for the future development of more advanced carrier systems to be

577 applied for health promotion and disease prevention. This review demonstrated that the
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578 intelligent delivery systems have the great potential to be the future trend to effectively improve

579 the quality and bioavailability of the bioactive compounds in functional foods.
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580 Acknowledgement

581 The financial supports of the National Natural Science Foundation of China (NSFC 31471577,

582 31772014) and the Beijing Nova Program (XX2018048) are gratefully acknowledged.

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855

856 Figure Captions

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857 Fig.1. Schematic representation of the physicochemical and physiological conditions in different

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858 regions of the human gastrointestinal tract. Oral pH is pH 7.4, and it contains many saliva

859 amylases. Stomach pH is pH 1-2, it has many pepsin proteases, some lipases and amylases.

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860 Intestinal pH is pH 6-7. The intestinal epithelium is composed of mucus barriers and cell layers.

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861 The permeation of some ingredients through the mucus is inhibited. The cells surface may have
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862 cell receptors and P-gp efflux pump proteins. The colonic pH is pH 7-8. It has many diverse

863 microorganisms and some strains secret the dextranase which can degrade dietary fibers.
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864 Fig.2. The structural composition of the small intestinal epithelium and transport mechanisms of
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865 nutrients through the intestinal absorption cells. The small intestinal epithelium mainly consists

866 of enterocytes for absorption of nutrients, goblet cells for secreting mucus barriers, M cells for
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867 immunologic function. There are four transport mechanisms including (A) Passive diffusion:
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868 transcellular diffusion, (B) Passive diffusion: paracellular diffusion, (C) Carrier-mediated

869 transport, (D) Receptor-mediated transport and (E) Efflux pump mechanism.
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870 Fig.3. The different active transcellular transport mechanisms of cellular internalization for
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871 foreign delivering particles. (A) Caveolae-mediated endocytosis depends on a multidomain

872 GTPase-dynamin. (B) Clathrin-mediated endocytosis is a widely shared pathway of nanoparticle

873 internalization. (C) Macropinocyosis displays a poor selectivity for engulfing nanoparticles and

874 the extracellular milieu. (D) Phagocytosis is an actin-based pathway taking place primarily in

875 professional phagocytes. The figure was modified according to reference (Yu, Yang, et al.,

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876 2016).

877 Fig.4. The illustration of various food intelligent systems. (A) Oral-responsive carriers: prolong

878 the flavor retention; (B) pH-responsive carriers: keep stable at stomach pH but release

879 specifically at intestinal pH 7; (C) Enzyme-responsive carriers: degraded by colonic enzymes

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880 and release specifically in colon; (D) Targeted-delivery carriers: a targeting molecule conjugated

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881 with carrier, which increases the bio-recognition with the receptor at the cell surface; (E)

882 Mucus-penetrating carriers: penetrate through the mucus barriers and arrive to the epithelial cells

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883 and (F) Mucoadhesive carriers: have a sustained release manner.

884 Fig.1.

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885

886 Fig.2.

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887
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888 Fig.3.
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890 Fig.4.

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893 Table 1: The comparison of structure, responsive mechanisms and effect for various responsive

894 delivery systems.

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895

Responsive
Responsiveness Structure Effect References
mechanisms

Oral responsive Pickering emulsion Promote the stability Have an on-demand (Doyennette, et
of flavor compounds release in mouth. al., 2014; Z.

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Complex coacervation during storage. Have a Prolong their retention Zhang, Zhang,
burst release in the time and provide the Decker, et al.,
mouth triggered by desired sensory 2015)

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amylase, temperature, experience
or pH

pH responsive Complex coacervation The structure Increase their stability (Ezhilarasi, et

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remained contact at at acidic and digestive al., 2013; W.
Spray drying acidic pH but ruptured enzymatic conditions. Liu, et al.,
at intestinal neutral Prevent the early 2016)
Layer-by-layer pH release at stomach.

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Specifically arrive to
Self-assembly
small intestine for
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further absorption.

Enzyme Pickering emulsion The wall materials Release specifically in (Kumar, et al.,
responsive such as resistant the colon for therapy. 2017; Situ,
Layer-by-layer starch or Konjac Work as the prebiotics. Chen, Wang, &
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glucomannan can be Li, 2014; Zeeb,

degraded by colonic et al., 2015)
microorganism
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enzymes such as
dextranase
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Receptor targeting Cross-linked Coupling a targeting Improve the cellular (T. Jiang, et al.,
biopolymer gels molecule at the uptake as well as the 2014; Yun, et
surface of carriers, absorption of bioactive al., 2013)
then the carriers will compounds
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have an enhanced
uptake via receptor
mediated
enterocytosis
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Mucus- Layer-by-layer Quickly and deeply Transport across the (Iglesias, et al.,
penetrate through the epithelium and arrive 2017; Lai, et
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Penetrating Complex coacervation mucus barriers with to the epithelial cells al., 2009)
reduced interaction for absorption and then
with mucin network largely enter the
systemic circulation

Mucoadhesive Layer-by-layer Increase the Have a prolonged and (Sheng, et al.,

interaction between sustained release 2015; Shrestha,
the carriers and the manner et al., 2015)
mucus layer, then
prolong the retention
time of the carriers on
mucus

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Highlights

Smart carriers responsive to GI conditions increased bioavailability of bioactives.

Mucus-penetrating carriers can overcome mucus barrier and increase cellular
uptake.

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Sites-specific and on-demand release is more efficient for bioactives absorption.
Physicochemical and physiological GI condition and microenvironment are

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summarized.
The absorption mechanisms for bioactives and carriers are discussed respectively.

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