Food Bioscience 43 (2021) 101258

Contents lists available at ScienceDirect

Food Bioscience
journal homepage: www.elsevier.com/locate/fbio

Different nano-delivery systems for delivery of nutraceuticals

Ladan Rashidi
Department of Food and Agricultural Products, Food Technology and Agricultural Products Research Center, Standard Research Institute (SRI), Iranian National
Standards Organization (INSO), PO Box 31745-139, Karaj, Iran

A R T I C L E I N F O A B S T R A C T

Keywords: The nutraceutical or ‘bioceutical’ is an active compound with a pharmaceutical and standardized nutrient, which
Nanoencapsulation has physiological benefits for human health, performance, and well-being. Nanoencapsulation technology has
Nutraceuticals received increasing attention for entrapping bioactive compounds into nanocarriers for their preservation against
Bioactive compounds
undesirable conditions, including gastrointestinal digestion and cellular metabolism; controlling their release,
Polyphenols
Nanocarriers
enhancing biodistribution and bioavailability of bioactive compounds and their delivery into the target site of the
organism’s body. This paper presents an overview of and discusses the different nanocarriers (food grade and
other nano-delivery systems) used for the encapsulation of bioactive compounds or nutraceuticals concerning the
advantages and disadvantages of their application. It is well-known that the commercialization of food products
containing nanocarriers having nutraceuticals is still in the primary stages of expansion, and risk assessment and
safety factors should be considered by national bodies before their widespread usage.

1. Introduction nanoliposomes, and nanocomplexation have been developed to protect

Nutraceuticals are especially natural materials or derived from nat­
ural sources, including vitamins, antioxidants, prebiotics, fatty acids,
minerals, polyphenols, phytosterols, probiotics, carotenoids, fibers,
essential oils, and bioactive peptides have received considerable atten­
tion due to their health benefits and nutrition for human consumption
(Fig. 1). These compounds can be added as ingredients to foods to
produce “functional foods” for improving human safety and health,
performance, and well-being (Pateiro et al., 2021). Nutraceuticals
derived from natural sources are quickly oxidized and unstable which
lead to limits their utilization as nutraceutical ingredients. A suitable
tool for the increase of bioavailability, durability, and adsorption of
nutraceuticals is encapsulation using nanotechnology methods (Ramlia,
Alib, Hamzah, & Yatim, 2021). Nanoencapsulation systems provide
several benefits including undesirable taste, odor, and color masking,
providing pH-triggered controlled release, improved stability, reducing
side effects, improved shelf life, providing moisture-triggered, protec­
tion against oxidation, preservation of volatile ingredients, protection
against enzyme degradation, and pH before reaching the target, pro­
tection the ingredients from different environmental parameters
including oxygen, heat, water and light, improved solubility of vitamins
(Kiss, 2020). The number of nanocarriers such as nanoemulsions,
biopolymer matrices, mesoporous silica nanoparticles, carbon nano­
tubes, dendrimers, solid liquid nanoparticles, magnetic nanoparticles,
valuable or active compounds at suitable quantities, shelf life, and
controlled release (Milincic et al., 2019). It is considered that these
nanocarriers should not modify the physicochemical and sensory spec­
ifications of the nutraceuticals or bioactive compounds.
The physicochemical properties of nano-delivery systems, such as
size, functionality, shape, charge and hydrophilicity/hydrophobicity of
bioactive compounds/nutraceuticals impress on the cellular uptake ef­
ficiency. These features should be taken into account for the marketing
of products produced with nanotechnology. For example, nanocarriers
based on their dimensions may easily permeate biological tissues, thus
disrupting cells’ usual function with adverse effects on human health.
Cellular uptake of bioactive species (such as ions and molecules) and
nanocarriers like nanoparticles is based on passive transport and active
transport which hydrophobic and small molecules can be penetrated in
the lipid bilayer via passive transport, while nanoparticles and polar
molecules can be internalized by the specific receptors via active
transport (Dima, Assadpour, Dima, & Jafari, 2020).
Therefore, each type of nanocarriers is specified by advantages and
deficiencies, bioavailability, degree of ensured conservation and trans­
fer of bioactive agents, ease of application, biodistribution, food matrix
compatibility, production and usage expenses, biodegradability, regu­
latory situation (A series of safety, environmental, and regulatory as­
pects which could influence human health and the environment should
be intently attended to) and biocompatibility (Dima et al., 2020).

E-mail addresses: l.rashidi@standard.ac.ir, ladan_rsh@yahoo.com.

https://doi.org/10.1016/j.fbio.2021.101258
Received 3 February 2021; Received in revised form 6 July 2021; Accepted 18 July 2021
Available online 23 July 2021
2212-4292/© 2021 Elsevier Ltd. All rights reserved.
L. Rashidi Food Bioscience 43 (2021) 101258

chemical structure, etc.), properties of the food matrix (including the

interaction between biocomponents), food storage conditions (including
thermal treatments, freezing, pasteurization, canning, etc.), mechanical
treatments (such as washing, cutting and homogenization), chemical or
biochemical treatments (including salting, esterification, fermentation,
etc.), processing level of food (which depends on the structure and food
composition matrix and processing technique), and characteristics of
nutraceutical delivery systems (including small size, control release, the
superficial electrical charge, and diversity of carrier materials) (Dima
et al., 2020). Results of external parameters studies on nutraceuticals
oral bioavailability showed that bioavailability is the complex system of
biological processes and physicochemical properties which help to
biomolecules distribution in the body for increasing therapeutic impact.
In addition, the study of uptake mechanisms of bioactive loaded nano­
carriers is important for both improving bioavailability and under­
standing the risk assessment of nanocarriers’ toxicity and also risks of
accumulation of nanocarriers as nanoparticles in tissues and organs.

3. Encapsulation techniques, advantages, and disadvantages

Encapsulation is one of the useful processes applied for covering

various materials in different matrices of gas/gaseous, liquid, and solid
in the food industry. The major objective of the encapsulation is coating
sensitive compounds or reducing side effects of some useful compounds
applied in high concentrations, which these compounds are located in
Fig. 1. Kinds of Bioactive compounds.
the core and coated by suitable wall materials. Encapsulation techniques
protect nutraceuticals or bioactive compounds from unbalanced and
This study will describe recent nano-delivery systems used to
unfavorable conditions, including pH, light, moisture, heat, chemical
encapsulate different nutraceuticals or bioactive compounds in the food
and biological degradation, and oxygen during storage, processing, and
industry. In addition, the advantages and disadvantages of the most
utilization (McClements, 2020; Kiss, 2020; Rashidi & Khosravi-Darani,
common encapsulation techniques and nano-delivery systems used to
2011). Wall materials have a critical role in the encapsulation tech­
encapsulate nutraceuticals are discussed. Besides safety issues on the use
nique because of their important effects on target delivery, bioavail­
of nanomaterials in food industry are described.
ability, biocompatibility, and protection of bioactive compounds. Also,
these materials should not have impact on flavor, color, texture, and
2. Nutraceuticals
other properties of foods. The important properties of suitable wall
materials contain a low cost, low viscosity, film-forming capacity, high
Nowadays, natural dietary agents are considered both by the general
solubility, low hydroscopy, high stability against the media of the tar­
public and researchers because of their properties to suppress cancers,
geted, high protection, abundant, nontoxic, and compatible via food or
prevent cancer creation, and reduce the risk of cancer development.
drug formulations (Delshadi, Bahrami, Tafti, Barba, & Williams, 2020).
These phytochemicals have low water solubility and poor stability lead
Several techniques are used for encapsulating bioactive agents which
to poorly adsorb by the human body. Nutraceutical such as polyphenols,
the preferred encapsulation technique depends on the bioactive com­
some special peptides, and essential oils are water-insoluble, unstable,
pound structure and its end use (Delshadi et al., 2020). The famous
and have low oral bioavailability and biodistribution, which these
encapsulation techniques are included supercritical fluids, inclusion
characteristics limit their biological activities (Shi et al., 2021).
complexation, nanoprecipitation, freeze-drying, spray drying, emulsifi­
Bioavailability of oral administration refers to the transfer of nutra­
cation, solvent evaporation, coacervation, ionic gelation, self-assembly
ceuticals or bioactive compounds through the gastrointestinal tract
of molecules, co-crystallization, and electrospinning which are
(GIT) stages and “absorption” is the second step of bioavailability and
described as follows:
also “bioaccessibility” is the first step of bioavailability. Polyphenols
Coacervation method is based on the interaction between two
have low bioavailability which is mainly because of the low absorption
oppositely charged polyelectrolytes in water for the formation of the
of them in the human gastrointestinal (GI) tract following consumption,
coacervate which can be used to encapsulate heat-sensitive ingredients at
high biotransformation in the gut, glycosylated type of polyphenols
room temperature but this method has difficulties in scaling up, the
compounds which reduce their diffusion across obstacles in the GI tract,
particle isolation procedure and uses large amounts of organic solvents.
and fast elimination from the human body (Milincic et al., 2019). In
Also, this method has advantages including simple preparation condi­
addition, some phytochemicals cannot be absorbed from enterocytes
tions, including low agitation and non-toxic solvent, high loading ca­
because they are unstable in the stomach (the acidic condition) or the
pacity, reduced evaporation losses, low temperature, no special
small intestine (alkaline situations). They are generally metabolized in
equipment is needed, and controlled release of active material (Ozkan,
the liver which helps their rapid excretion (Milincic et al., 2019). Some
Franco, De Marco, Xiao, & Capanoglu, 2019).
of the bioactive compounds can be subjected to chemical and
In the solvent emulsification/evaporation, the lipid dissolves in the
biochemical transformations in GIT fluids. For example, curcumin de­
water-immiscible solvent as chloroform or toluene and then is emulsi­
grades in the alkaline environment and the exposure of a certain enzyme
fied in an aqueous phase before evaporation of the solvent under
(Rafiee, Nejatian, Daeihamed, & Jafari, 2019), proteins and peptides
reduced pressure. Then, lipid precipitation upon solvent evaporation,
may be hydrolyzed in acidic situations and also under the act of pro­
therefore nanocarriers are formed. Merits of this method include lab-
teolytic enzymes (Akbarbaglu et al., 2019). In addition, there are
scale acceptability, higher stability, obtaining the smallest particle size
external parameters which can influence on the bioavailability of
but its demerits are the use of toxic solvents, increase of lipid content
nutraceuticals, including physicochemical characteristics of nutraceut­
leads to the increase of polydispersity index and particle size distribution
icals (such as the solubility, the physical state, the lipophilicity, the
(Ozkan et al., 2019).

2
L. Rashidi
Inclusion complexation method uses for encapsulation of volatile
organic molecules and defines the molecular association between wall
and core, attributed to as cavity-bearing substrate and ligand, respectively.
In addition, known as the molecular inclusion technique which takes
place at molecular levels and produces nanocapsules with sizes from
0.001 to 0.01 μm. Inclusion complexation technique has advantages
including simplest formulate, reduce evaporation and stabilize flavors,
reduce hemolysis, enhance solubility, stability, and bioavailability while
its disadvantages are high cost of preparation, stability issues, difficulty
in incorporating into the formulation of dosage forms, reproducibility of
physicochemical properties, small dose nutraceuticals are complexed,
and scale-up of the manufacturing process (Ozkan et al., 2019).
Nanoprecipitation or solvent displacement method is used for lipo­
philic nutraceuticals in which a preformed polymer and the nutraceu­
tical are dissolved in an organic solution, then organic phase is poured
into aqueous medium containing a surfactant. Nanoprecipitation is a
versatile technique for preparation of different types of polymer nano­
particles with suitable controlled particle size, surface properties, and
size distribution. A disadvantage of this method is the low concentration
of polymer leads to a problem in nanoparticle recovery in the final
dispersion (Tiruwa, 2015).
The reverse - phase evaporation method is applied for the prepara­
tion of liposomes in which the lipid mixture is added to the organic
solvent, then solvent under reduced pressure using rotaevaporation is
removed. The lipids are re-dissolved in an organic phase for formation
the reverse-phase vesicles. The limitations of this method are the pos­
sibility of remaining solvent after evaporation, time-consuming, and risk
of high temperature exposure leading to phospholipid/nutraceutical
damage, and decreasing of encapsulation and influencing carriers’ sta­
bility (Tiruwa, 2015).
Freeze drying or lyophilization contains multi stage processes,
including freezing, sublimation, desorption, and finally storage steps. In
this method, ice is sublimed for production of a gas under pressure and a
small amount of heat (low operating temperature without the existence
of air) which can be used for heat-sensitive materials for their storage for
a long time but this technique is more expensive and needs a long
dehydration time. Also, this technique creates the porous structure of
freeze-dried powders because of the ice sublimation during the process
and the freeze-dried powders should be crushed or ground after drying,
therefore control of particle size is another problem of using this method
(Ozkan et al., 2019).
Spray drying is the oldest technique used for encapsulation of
nutraceuticals related to the atomization of the liquid into dry powder
by an injector as a hot drying gas stream comprised of three steps
including homogenization of feed liquid as a core wall and wall material
with an atomizer, drying of feed solution using a hot gas carrier for
achieving the evaporation of the solvent and collection of dry particles
by cyclones or filter. This technique is simple, rapid, economic, easy to
scale-up, reproducible, obtain solid particles with low moisture content,
and continuous. The disadvantages of this method include high con­
sumption of energy, use of high temperature leads to damage sensitive
compounds, low product yield, the low water solubility of proteins and
polysaccharides leads to limitations for applying spray drying, lack of
controlling the droplet size and shape, high cost, and time aspects
(Ozkan et al., 2019).
The salting out method is considered as a modification of the
emulsification/solvent diffusion which is based on the separation of the
water miscible solvent from the aqueous medium through the salting out
impact. Salting out technique does not use of toxic organic solvents.
Therefore, polymer and nutraceutical are dissolved in a solvent that
emulsified into the aqueous solution containing the salting out agent as
electrolytes, including sodium chloride and calcium chloride. This
method uses electrolytes for the separation of organic solvent and
minimizes stress to protein. The solvent is removed by filtration or
evaporation. The advantages of this technique for encapsulation are low
cost, high particle quality with small size, good yield and rapid
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Food Bioscience 43 (2021) 101258
solubility, and good stability. The disadvantages of this method are its
application for lipophilic nutraceuticals and using high volumes of water
for elimination from suspension, and reducing efficiency (Tiruwa,
2015).
The supercritical fluid technique is an alternative method in which
organic solvents are not applied. Supercritical CO2 is widely applied as a
supercritical fluid due to its mild critical situations, which is not toxic,
non-flammability, and has a low price. The advantages of this technique
are control of particle size and morphology, preventing of losing or
degradation of biological activities of thermos sensitive nutraceuticals,
high encapsulation efficiency. The limiting parameter of using this
method is the selection of the supercritical process on the basis of the
solubility of active material to be encapsulated and polymer matrix in
the supercritical fluid (Ozkan et al., 2019).
Ionic-gelation or polyelectrolyte complexation is based on the
capability of crosslinking polyelectrolytes in the presence of multivalent
ions and is applied for extrusion or emulsification/gelation which
extrusion method uses for fabrication of spherical gel particles using
dripping an aqueous polymer solution through the syringe needle or a
nozzle into CaCl2 having a gelling bath and emulsification/gelation
method produces an emulsion such as a hydrophobic active component
in the polymer solution followed by dripping into the calcium solution.
This technique is simple, and easy due to its low cost and does not need
special equipment, organic solvents, high encapsulation efficiency and
high temperature. Also, this method uses reversible physical cross­
linking instead of chemical crosslinking, therefore there is not possible
toxicity of reagents (Ozkan et al., 2019).
The liposomal entrapment method can be used for encapsulation of
enzymes, hormones, and vitamins which uses one or more layers of
lipids which is not toxic. Liposomes are composed of lipid bilayers and
easy to make and can be stored by freeze drying. Disadvantages of
liposomal entrapment are scaling up, poor physical and chemical sta­
bility, lipid oxidation, producing a wide range of particle size distribu­
tions, leakage and fusion of encapsulated nutraceuticals or bioactive
agents, also some of the phospholipids used in this method undergo
oxidation and hydrolysis-like reaction which leading to decrease of
liposome shelf life (Ozkan et al., 2019).
Electrospinning is used for the incorporation of nutraceuticals or
bioactive agents within electrospun fibers which enhances functional
materials performance in the food industry. This technique can produce
nano-scale polymer fibers. The advantages of this method are ease of
use, cost-effective of synthesizing nanofiber, easy encapsulation of
bioactive compound into nanofibers, does not need heat treatment, and
does not impact on sensory qualities of products (Castro Coelho,
Nogueiro Estevinho, et al., 2020).
Self-assembly is another encapsulation technique with advantages,
including the production of small nanoparticles, high encapsulation ef­
ficiency, and high stability but its disadvantages are the problem to
control the size and shape of nanoparticles (Castro Coelho, Nogueiro
Estevinho, et al., 2020).
The overview of applying different encapsulation techniques for
nanoencapsulation of various bioactive compounds is presented in
Tables 1–5.
4. Food grade delivery systems
4.1. Protein - based delivery systems
Protein nanocarriers can be obtained from bacterial, plant, animal,
and fungal sources and are applicable for the delivery of both hydro­
philic and hydrophobic nutraceuticals (bioactive agents). Gelation,
extrusion, emulsification, inclusion complexion, coacervation, and
spray drying are useful techniques for producing proteins based on
nanodelivery systems such as nanoassemblies, hydrogels, micelles,
films, hydrocolloids, and micro- and nanoparticles (Assadpour & Jafari,
2019). Gelatin, casein, whey proteins, albumin, collagen, and elastin
L. Rashidi
from animal sources and soy glycinin, and wheat gliadin and zein from
plant sources are commonly applied as protein carriers (Assadpour &
Jafari, 2019). Meat proteins including gelatin and collagen, especially
gelatin derived from collagen, used for encapsulation of nutraceuticals
due to their biocompatibility, high-temperature stability, biodegrad­
ability, ease of bridge, and safety but disadvantages of using them are
low mechanical strength and rapid degradation speed (Fathi, Donsi, &
McClements, 2018; Hong et al., 2020).
Milk proteins contain different molecular structures and functional
features. Casein is poorly water-soluble and has high-temperature sta­
bility. It has four main protein fractions including αS1, αS2, β, and
κ-casein but tends to aggregate near to their isoelectric point and in the
attendance of multivalent counter-ions which limited their usage in
some foods. β-casein has strong amphiphilic property for encapsulation
of both hydrophobic and hydrophilic nutraceuticals. Whey proteins
possess advantages for encapsulation of nutraceuticals, including the
ability of formation hydrogels, and their surface activity but in higher
temperatures of around 70 ◦ C undergoe thermal denaturation (are not
thermostable), therefore, it can be used to encapsulate heat-sensitive
nutraceuticals at ambient temperature. In upper than 70 ◦ C, the pro­
teins relatively unfold and connect together via hydrophobic attraction
and disulfide bond generation. Different fractions of whey proteins
include α-lactoglobulin (α-Lg), β-lactoglobulin (β-Lg), and bovine serum
albumin (BSA) which all of them can be used for encapsulation of
bioactive compounds (Fathi et al., 2018). β-LG uses for encapsulation of
low molecular acid-sensitive bioactive compounds for its stability in
acidic media and proteolytic enzymes in the stomach. Egg proteins like
lysozyme, ovomucin, albumin, livetins, etc. can be applied for encap­
sulation purposes but egg ovalbumin is further commonly used for
encapsulation due to its relatively resistance to pepsin digestion in the
stomach. Albumin can be used for water-soluble bioactive compounds.
Zein proteins are found in corn and constitute of three-quarters hydro­
phobic and one-quarter hydrophilic amino acid residues lead to be
insoluble in water and soluble in some organic solvents like ethanol. It
can be used for encapsulation of water-insoluble bioactive compounds
but it shows the limited digestion in the stomach leads to the use of it for
encapsulation of acid-sensitive compounds. Soy proteins isolated from
soybeans and show surface activity and structure formation lead to
development delivery systems and encapsulation but they should be
carefully purified to prevent excessive protein aggregation and dena­
turation due to loss of their functionality. Pea proteins consist of
different globular proteins such as albumins, gluteins, and globulins (the
major fraction of pea proteins consists of three types including legumin,
vicillin, and convicillin) which have surface-active, and structure for­
mation properties. Also, a recombinant protein can be applied for
encapsulation due to its higher purification than natural proteins but its
consumer acceptability and economical production should be consid­
ered (Fathi et al., 2018).
Protein-based delivery systems show advantages including low
toxicity, stability, the possibility of surface modification of protein
nanoparticles, and easily biodegradability. The demerits of proteins or
peptides used for delivery of nutraceuticals include low bioavailability,
rapid metabolism, conformational changes, non-covalent complexation
with blood products, opsonization, and metabolic liability which using
different encapsulation techniques can be overcome to their application
limitations as nano-delivery systems.
Table 1 presents an overview of protein-based nanocarriers used for
the encapsulation of different nutraceuticals using various encapsula­
tion techniques.
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Food Bioscience 43 (2021) 101258
4.2. Lipid-based delivery systems
The use of lipid-based nanodelivery systems is an advantage for the
lipid-based nutraceuticals which are hydrophobic compounds including
fatty acids (especially ω-3 and conjugated linoleic acid (CLA)), carot­
enoids (lycopene, β-carotene, lutein), antioxidants (polyphenols
including oleuropein, caffeic acid, gallic acid, tocopherols, flavonoids),
fat-soluble vitamins (A, E, D, and K) and phytosterols (stigmasterol,
β-sitosterol, campesterol), to be entrapped in the liquid form. Lipid-
based nanostructures applied for bioactive compounds of foods and
nutraceuticals’ delivery include lipid nanospheres, especially lipid
nanoparticles, nanoliposomes, nanocochleates, and archaeosomes. The
principal techniques employed to formulate a lipid-based delivery sys­
tem are emulsification, oil-in-water (O/W) nanoemulsions or micro­
emulsions, multilayer emulsions, filled hydrogel particles, liposomes, or
solid lipid nanoparticles (Assadpour & Jafari, 2019). In the following,
the three most important lipid-based nanocarriers are described in
detail. In addition, Tables 2a, 2b, and 2c present the lipid-based nano­
delivery systems including nanoemulsions, solid lipid nanoparticles
(SLNs), and nanoliposomes applied for the encapsulation of
nutraceuticals.
4.2.1. Nanoemulsions
Nanoemulsions are heterogeneous systems consisting of dispersions
of nano-scale droplets formed by shear-induced rupturing. They contain
two immiscible liquids, in which one liquid phase is dispersed as drop­
lets into a continuous liquid phase and stabilized with an emulsifier
(Peng, Meng, et al., 2019). Therefore, the main three components of
nanoemulsions are oil, surfactant or cosurfactant, and aqueous phase, in
which oil can be of any type, such as olive oil, castor oil, corn oil, sesame
oil, coconut oil, linseed oil, medium-chain triglyceride oil (MCT), min­
eral oil, peanut, or evening primrose. Nanoemulsions are distinguished
as an O/W (oil in water) or W/O (water in oil) emulsion with mean
droplet size ranging from 20 to 200 nm which are generally recognized
as safe (GRAS) by the The Food and Drug Administration (FDA), 2014
and can be used for human consumption. Table 2a shows nanoemulsion
carriers applied for the encapsulation of bioactive agents. In the syn­
thesis of nanoemulsions, the selection of emulsifier type is highly
important for controlling interfacial properties, including thickness,
droplet, rheology, and charge. It was reported that using double-layer
techniques (oil droplets coated by double-layered interfacial mem­
branes) for forming W/O/W multiple emulsions could efficiently coat oil
particles during emulsification (Peng, Meng, et al., 2019). Nano­
emulsions do not sediment or cream since the Brownian motion is
greater than the small creaming rate induced by gravity. The most
common methods for the preparation of nanoemulsions include
high-pressure homogenization and microfluidization, but other methods
as ultrasonication and in-situ emulsification are applied as well (Peng,
Meng, et al., 2019).
Advantages of using nanoemulsions include that they can show high
kinetic stability against flocculation and creaming, possess somewhat
thermodynamic stability and potential application for personal and
health care products and transport easily through the cell membrane
which leads to increase their bioavailability, biocompatibility, the sur­
face groups can be conjugated with targeting ligands. Although, disad­
vantages of using nanoemulsions include the high cost of production and
finding a food grade surfactant and also they are almost thermody­
namically unstable systems due to different factors including environ­
mental factors and intrinsic factors such as coalescence, creaming,
Ostwald ripening, flocculation, etc., immediate bioactive compounds
L. Rashidi Food Bioscience 43 (2021) 101258

Table 1
Overview of bioactive compounds encapsulated by protein - based delivery systems.
Encapsulating Materials Nutraceutical Study/Target Encapsulation Size (nm) Encapsulation References
Technique Efficiency (%)

Zein NPs./Fucoidan & Curcumin Characterization of NPs, Release in Antisolvent – 81.07 Zhang et al. (2021)
Sulfated simulated gastrointestinal digestion precipitation
polysaccharide
Zein Nanofibers Ascorbyl Characterization of nanofibers, Electrospinning – 22.5–65.5 Miri, Habibi Najafi,
palmitate (AP) Increase of antioxidant activity of AP Movaffagh, and Ghorani
(2021)
Cationic 30 mer alpha tri- Cell viability, Immunocytochemistry Condensation 43 – O’Doherty et al. (2020)
amphipathic peptide calcium staining in MG-63 cells,
(RALA) phosphate Mineralization in porcine
(α-TCP) mesenchymal stem cells (PMSCs)
Zein nanofibers: Carvacrol Increase thermal & Mechanical Electrospinning 103 & 17 40 ± 1.9 to 81 ± Altan and Cayir (2020)
Tributyl citrate & stability, low water barrier properties 1.7
Tween 80
Gelatin NPs: porcine Buriti Oil Antimicrobial activity on Emulsification 51 OPG:86.80 Castro, Passos, et al. (2020)
gelatin (OPG) & Pseudomonas aeruginosa, Klebsiella followed by Freeze OAG:7191
sodium alginate pneumonia, and Staphylococcus drying
(OAG) aureus
L-arginine (Arg)- or L- Curcumin Characterization of NPs, In vitro Self-assemble 82–110 Curcumin: Du et al. (2020)
lysine (Lys)- Egg white release in simulated gastrointestinal, 81–91,
functionalized derived peptide Oral delivery EWDP:35–74,
chitosan–casein NPs (EWDP) Arg–CS–CA;
Curcumin:
76–87,
EWDP:48–87,
Lys–CS–CA Ps
Gelatin Nanofiber Curcumin Characterization of nanofiber, Sequential 184–236 89.05–92.57 Wang, Li, Zhang, Feng, and
Release from gelatin film, antioxidant electrospinning Zhang (2020)
activity of released curcumin during
96 h
Whey Protein NPs Olive Leaf Characterization of NPs & EE% Electrospraying 232.3–659.8 36.66–83.66 Soleimanifar, Jafari, and
Extract Assadpour (2020)
Zein NPs β-carotene Characterization of NPs & EE%, Electrospray 599–906 61.37–81.76 Mahalakshmi, Leen, Jeyan,
Release in gastrointestinal Drying and Anandharamakrishnan
(2020)
Gelatin NPs (GNPs) Genistein (GEN) Stability at pH = 2, EE% Modified two-Step 273–391 90 Song et al. (2019)
& Icariin Desolvation
Nanogels & Lysozyme Tea polyphenols DPPH and ABTS-scavenging rates of Self- Assembly 420–720 89.05 ± 3.14 Liu, Zhang, Kong, Zhang, and
(Ly) & (TP) the TP-loaded NGs, Anticancer Yang (2019)
Carboxymethyl activity on HepG2 cells
Cellulose (CMC)
Albumin Micelle Curcumin Characterization of NPs/Cytotoxicity Micelle 22.1 98.2 Motevalli et al. (2019)
effects on NPs on MCF-7 cell line
The hydrophobic cores Curcumin & Characterization of NPs, Release in Anti-solvent 100–200 Curcumin: 96.2 Yan et al. (2019)
of Zein NPs & EGCG simulated gastrointestinal tract, EGCG: 77.9
Caseinate shell DPPH radical scavenging capacity of
the NPs
Zein NPs Saffron Characterization of NPs, Stability of Electrospun/ – 74–97 Alehosseini,
encapsulated extract at UV light, & Electrospray Gómez-Mascaraque, Ghorani,
different pH (2, 7.4) and López-Rubio (2019)
Casein micelles or EGCG & folic Characterization of NPs, EE%, Self-assemble,/ 66.2 85 Malekhosseini et al. (2019)
Casein NPs acid Release in acidic & alkaline media, Anti-solvent
Stability in Thermal treatment
Casein micelles Quercetin The effect of pH & Concentrations of Self-assemble 182.2–334.4 more than 97 Ghatak and Iyyaswam (2019)
casein & additives & CTAB, EE%
β-Lactoglobulin NPs Quercetin Characterization, Digestion by Anti-solvent 180–298 13.9 Chavoshpour-Natanzia and
proteases, Release in simulated Sahihi (2019)
gastrointestinal tract,& colon &, EE%,
Release Kinetic model

release, and instability upon storage (Peng, Meng, et al., 2019).
4.2.2. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers
(NLCs)
The lipidic phase of nanostructured lipid carriers contains the solid
lipid (fat) and liquid lipid at room temperature. The solid lipid nano­
particles (SLNs) are lipid-based delivery systems able to solubilize
lipophilic nutraceuticals containing a core matrix (including waxes,
fatty acids and acylglycerols) and are stabilized by surfactants (such as
sphingomyelins, phospholipids, bile salts and sterols). In comparison
with other lipid-based nanocarriers, including nanoemulsions and li­
posomes, SLNs possess advantages such as robust protection against GI
tract degradation, stability to labile hydrophobic compounds, and pro­
vide controlled release profiles of a given nutraceutical (Nandvikar,

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Table 2a
Overview of bioactive compounds encapsulated by lipid – based systems (Nanoemulsions).
Encapsulating Materials Nutraceutical Study/Target Encapsulation Size (nm] Encapsulation References
Technique Efficiency (%]

Nanoemulsions (O/W): WPI, Resveratrol Chemical stability, Effect of oil High Pressure 540–570 98 Cheng, Zhang, Li, Duan,
Gum Arabic, Sunflower, type Homogenization and Liang (2021)
Origanum, & Peppermint Oils
Nanoemulsion (O/W): Oleic Zataria Antiparasitic effect Ultrasonic 73–82 – Yazdi, Haniloo, Ghaffari,
acid &Tween 80 multiflora Homogenization and Torabi (2020)
essential oil
Nanoemulsions (O/W): BSG, Vitamin D3 & Characterization of Ultrasonic 115–385 – Gahruie et al. (2020)
WPC, Tween 80, Canola oil Saffron petal nanoemulsion, In vitro release Homogenization
extract
Nanoemulsions (W/O/W): Mentha piperita Characterization of Homogenization 108.66, 80.5, 88.7, & 90.8 (Roshanpour et al.,.
chitosan, Alyssum extract (MPE) Nanoemulsions, EE%, Release, 70.81, & 2020)
Homolocarpum gum (AHG) Oxidative stability of soybean oil 65.18
& complex of Chitosan & contains W/O/W/MPE
AHG (CCA), Span 80,
Soybean oil
Nanoemulsions (O/W): Tween Vitamin D3 (Vit Effects of storage & Ultrasonic 119.3 – Mehmood and Ahmed
80 & Soya-lecithi-based food- D) Temperature, Oxidative Stability Homogenization (2020)
grade canola oil contains O/W/Vit D
Nanoemulsions (W/O/W): Ferula persica Characterization, EE%, The Homogenization 76.61 ± 0.3 64.1–93.3 Estakhr, Tavakoli,
Locust bean gum & Chitosan, extract (FPE) biological effect of FPE to 147.91 ± Beigmohammadi, Alaei,
Soybean oil, Span 80 0.4 and Mousavi Khaneghah
(2020)
Nanoemulsions (O/W): Hyssop extract The effect of O/W/HE on Ultrasonic 56.713 ± 88.36 ± 2.4 Savadkouhi, Ariaii, and
Lepidium perfoliatum seed (HE) oxidative stability of Soybean oil Homogenization 1.48 Charmchian Langerodi
gum & Orchis mascula, (2020)
Soybean oil,
Nanoemulsions (O/W): Tea β-Carotene (BC) In vitro digestion assay, Stability High-Pressure lower than – Meng et al. (2019)
polyphenols-β-carotene (TP- of O/W at different Homogenization 100
BC), Polysorbate 80 temperatures, In vivo absorption
Nanoemulsions (O/W): Capmul Vitamin E Narrow beam, Muscular Homogenization 38.70 ± 82.71 ± 9.14 Gaba et al. (2019)
MCM as oil, & Tween 80 coordination, Grip strength, 3.11
Forced swimming tests, &
Akinesia test in a rat model
Nanoemulsions (W/O/W): Gallic acid Stability during storage, Homogenization 98–577 & – Gharehbeglou, Jafari,
Double Emulsions Pectin- Characterization of W/O/W 100–1520 Hamishekar, Homayouni,
WCP, PGPR, Tween 80 and Mirzaei (2019)
Nanoemulsions (W/O/W): Arbutin & Creaming stability & Sensory Homogenization 355.98 ± Arbutin: 91 ± 3 Huang, Belwal, Liu,
Arbutin, Gelatin, Hydrophobic evaluation beverage, Release 10.44 Coumaric acid: Duan, and Luo (2019)
Polyglycerol Polyricinoleate Coumaric acid kinetics in simulated 82 ± 2
(PGPR) gastrointestinal
Nanoemulsions (O/W): Birch Leaf The creaming stability, Homogenization – 80–90 Pulit-Prociak, Kabat,
Cholesterol, Soy Lecithin & Extract characterization of Węgrzyn, Zielina, and
Water nanoemulsions, EE% Banach (2019)
Nanoemulsions (O/W): WPI, Curcumin The encapsulation stability, Ultrasonic PE:359 ± PE:78 Carpenter, George, &
sodium alginate, olive oil, antioxidant activity, release Homogenization 5.6 to SE:100 Saharan. (2019)
Primary emulsion (PE) & properties of curcumin, SE:841 ±
secondary emulsion (SE) Characterization 13.4
Nanoemulsions (W/O/W): Basil Rosemary Antioxidant properties, Homogenization 154.69, 58.71, 66.39, & Rashidaie Abandansarie,
seed gum, Soy-bean protein extract (RE) Antibacterial activity, The 126.48, & 61.35 Ariaii, and Langerodi
isolate & combination of amount of phenolic compounds 139.52 (2019)
them of W/O/W/RE
Nanoemulsions (O/W): Gum Fish oil Effect of rosemary extract Ultrasonic 36.67–82 87.17 Moghadam, Pourahmad,
Arabic, Tween 80 encapsulated nanoemulsion on Homogenization Mortazavi, Davoodi, and
antimicrobial and antioxidant Azizinezhad (2019)
properties of rosemary and shelf
life of meat
Nanoemulsions (O/W): CaCl2, Resveratrol Effect of protein stabilized O/W High-pressure 130–550 63–74 Zhang, Fan, Li, Chen, and
WPI, Gum Arabic, Sunflower, on oxidative stability of homogenization Liang (2019)
Tween 80 sunflower oil

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Table 2b
Overview of bioactive compounds encapsulated by lipid – based systems (SLNs, & NLCs).
Encapsulating Materials Nutraceutical Study/Target Encapsulation Size (nm) Encapsulation References
Technique Efficiency (%)

NLCs:Precirol ATO 5, Olive oil, Oleuropein Improve antioxidant Hot Melt 150 99.12 Huguet-Casquero,
Tween 80 efficiency, In vitro assay on Homogenization Moreno-Sastre,
A549 & CuFi1 Lung López-Méndez, Gainza,
Epithelial Cell Lines and Pedraz (2020)
SLNs: Precirol ATO, Pluronic Curcumin Curcumin bioavailability, In Precipitation 159–302.5 68.62 Minafra et al. (2019)
F68, & Dimethyldioctadecyl- vitro Cytotoxicity effect on
Ammonium Bromide breast cancer cell lines
NLCs: Glyceryl Monooleate, Curcumin Release pattern, photo- High Shear Hot 101.80 ± 47.11 & 51.55 Kamel, Fadel, and Louis
Geleol, Glyceryl Dibehenate, cytotoxic anticancer effect Homogenization 1.41 to (2019)
Glyceryl Distearate, Tween 80, on breast cancer cells 265.70 ±
& Olive oil 19.9
SLNs: Trilaurin, Tristearin, Curcumin Characterization of SLN, EE Cold Dilution of 169.8 ± 4.7 78 ± 1.3 to Chirio et al. (2019)
Myristic acid, Glyceryl %, Cytotoxicity effects on Microemulsion to 215.3 ± 70.±2.1
Monostearate, Ethyl Acetate, pancreatic adenocarcinoma 5.5
Benzyl Alcohol, Triacetin, cell lines, In vivo study on
Butyl lactate, & polysorbate Wistar healthy rats
SLNs: Cocoa Butter, Stearoyl-2- Epigallocatechingallate Degradation during storage Hot 108–122 68.5 Shtay, Keppler,
Lactylate (SSL) & Mono- & & digestion under simulated Homogenization Schrader, and Schwarz
Diglycerides, Lecithin gastrointestinal pH (2019)
(Phospholipon® 90G) conditions

Lala, & Shinde, 2019) . Disadvantages of using SLNs in the food industry
include loss of bioactivity of heat-labile compounds during their prep­
aration, low encapsulation load, the possibility of explosion during
storage. The NLC produces by mixing various lipid molecules including
solid lipids with liquid lipids on the basis of preparation methods applied
for SLN. In NLC, the encapsulation of nutraceuticals increases and
expulsion phenomena during storage is limited by inhibition of perfect
crystals formation. Advantages of NLCs include possibility of targeted
and sustained nutraceutical release, improved physical stability, easier
to validation, the possibility free of using solvent in the process, appli­
cable for both hydrophilic and hydrophobic nutraceuticals, increase of
loading capacity, biodegradability, and biocompatibility of used lipids
in NLCs. Disadvantages of NLC include the burst release and low sta­
bility against aggregation, irritation and sanitizing action of some sur­
factants. In Table 2b, recent studies in which solid lipid nanoparticles
(SLNs) and nanostructured lipid carriers (NLCs) were applied for the
encapsulation of nutraceuticals are presented. Both SLNs and NLCs are
lipid-based nanocarriers, which are very suitable for food applications
since no organic solvent is used in their making (Chirio et al., 2019).
There are three types of NLC structures based on the formulation
composition and the production parameters including imperfect,
amorphous, and multiple types. Methods for NLCs or SLNs production
include microemulsion technique, hot and cold homogenization
method, emulsification solvent diffusion method, solvent
emulsification-evaporation method, solvent injection method or solvent
displacement method, phase inversion technique, membrane contractor
technique, and multiple emulsion method (Chirio et al., 2019).
Advantages of the use of SLNs include biocompatibility, bioavail­
ability, ease of scale-up, good tolerability, avoidance of the organic
solvents usage during preparation, high loading capacity, controlled
release, and physical stability. Disadvantages of SLNs are their tendency
for particle aggregation, easy clearance by the reticuloendothelial,
bioactive components leakage after polymorphic conversion during
storage, uncertain diffusion of the bioactive agents in the lipid matrix of
the vector, unpredictable gelation tendency, and low loading capacity.
NLCs have advantages for overcoming the shortcomings of SLNs, which
include high loading capacity of bioactive compounds, preventing par­
ticle aggregation and also happening of leakage via crystal trans­
formation during storage, preparation, and processing (Nandvikar et al.,
2019).
4.2.3. Liposomes
Liposomes are ideal carriers consisting of an aqueous core sur­
rounded by natural or synthetic phospholipids applied for hydrophobic
and hydrophilic nutraceuticals. Hydrophobic nutraceuticals are gener­
ally entrapped within lipid bilayer, and hydrophilic nutraceuticals are
likely to be entrapped within the core. Due to the low stability of lipo­
somes during administration and storage, liposomes with modified
surfaces by several molecules, including surfactants, have been devel­
oped and applied for both food and pharmaceutical industries (Zhou
et al., 2021).
Emulsification, pressure extrusion, thin-film dispersion, pH gradient,
high-pressure homogenization, centrifugation, reverse evaporation,
melting, and freeze-drying technologies are applied for the preparation
of liposomes. Liposomes are biocompatible and bioavailable carriers,
and external factors, including temperature, light, enzymes’ presence,
and pH can liberate the sudden release of their content by interfering
with membrane stability, causing lipid layer disruption and quick drug
release, non-toxic, encapsulation both of hydrophilic and hydrophobic
bioactive compounds, increase solubility of nutraceuticals. Disadvan­
tages of liposome application include low encapsulation yield and the
physical and chemical instability, low nutraceutical transport rate, dif­
ficulty of binding ligands to the surface, rapid clearance of mononuclear
phagocytic system (Zorkina et al., 2020). Nanoliposomes are bioavail­
able and biocompatible and can be used for both hydrophobic and hy­
drophilic compounds and protected them from enzymatic destruction in
the body. Disadvantages of nanoliposomes are included expensive lipid
components and instability of lipid components in acidic environments
(Zorkina et al., 2020). Table 2c presents an overview of nutraceuticals
encapsulated by the liposome carriers.

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Table 2c
Overview of bioactive compounds encapsulated by lipid – based deliver systems (liposomes).
Encapsulating Materials Nutraceutical Study/Target Encapsulation Size (nm) Encapsulation References
Technique Efficiency (%)

Liposomes: Rhamnolipid, Curcumin Study release & stability electrostatic 412.9 to – Zhou et al. (2021)
phospholipids, chitosan interaction 639.8
Liposome: Phospjatidylcholine, Stingless bees Physicochemical Thin-film hydration 275.5 66.9 Ramlia, Alib,
Cholesterol Propolis extract characterization of Hamzah, & Yatim,
liposome (2021).
Liposomes decorated by chitosan: Egg Cinnamaldehyde Antibacterial efficiency Ethanol injection 400–600 38–50 Wang et al. (2021)
yolk phospholipid, Peptone, Beef
extract, Tween 80
Liposomes, Transfersomes & Sambucus Ebulus Characterization of Thin-Film 49 ± 1.52 to 75–85 Păvăloiu et al.
Ethosomes: Phosphatidylcholine, leaves extract liposomes, EE%, In vitro Hydration, 190 ± 2.53 (2020)
Cholesterol, & Sodium cholate (SELE) release Ultrasound
Treatment &
Extrusion; & Cold
Method
Liposome: WPC, Pectin, & Sodium Trifolium Characterizations of six Thin Film Hydration 282.5–491.2 85–91 Sayyed-Alangi and
Azide Resupinatum Sprout formulations of Nematzadeh (2019)
Methanolic Extract liposomes
Lipoid S100-liposomes & Cholestrol Estragole, Characterization of Ethanol injection – More than 90 % (Hammoud,
eucalyptol, liposomes, EE%, Gharib,
isoeugenol, Release, Stability Fourmentin,
pulegone, terpineol, Elaissari, &
& thymol Greige-Gerges,
2019)
Liposome: Chitosan coated Liposomal: Vitamin D3 & Enhance Microfluidic 90 and 250 88.4 & 94.7 (Dalmoro et al.,
Phosphatidylcholine, Choline Basis, vitamin k2 Mucoadhesiveness & 2019)
Cholesterol stability of liposmes
Liposome: Lecithin, Phenolic- Pistachio Hulls The phytochemical Thin Film Hydration 96.3 ± 7.18 38.4 ± 2.67 Oskoueian et al.
Enriched Fraction analysis (2019)
Liposome: Phospholipids from Rice Quercetin Characterization, EE%, Thin Film & 157.33 ± 84.92 ± 0.78 (Rodriguez,
Bran, Soy Lecithin & Egg Yolk Storage stability, Sonication 23.78 Almeda, Vidallon,
Release in simulated & Reyes, 2019)
gastrointestinal fluid
Liposome: Cholesterol, Soybean Ascorbic acid In vivo efficiency, Drug Thin Film Hydration 161 ± 1 to 17.8 ± 0.6 to 58.1 (Maione-Silva et al.,
Phosphatidylcholine, 1,2-Dioleoyl- flux, Stability 190 ± 3 ± 4.0 2019)
3-Trimethylammoniopropane &
1,2-Distearoyl-sn-glycero-3-
phospho-(1′ -rac-glycerol)
Liposome: β-Lactoglobin-Liposome Vitamin A In vivio bioavailability Thin Film Dispersion – With β-Lg: 50.17 (Rovoli, Pappas,
Complex: in mice, EE%, & Freeze Drying Without β-Lg: Lalas, Gortzi, &
Phatidylcholine (PC from egg yolk)/ characterization of 50.64 Kontopidis, 2019)
Cholesterol (CH) with the molar liposomes
ratios: PC/CH
Liposome: Lecithin, Cholesterol, & EGCG & quercetin Characterization & EE% Thin Film Hydration 111.10 ± 64.05 ± 1.56 Chen et al. (2019)
Tween 80 0.52
Liposome: Lipids- Curcumin Sustained & prolonged Thin Film Hydration 203.02 ± 4.1 76.48 ± 1.2 to Choudhary,
Phosphatidylcholine, & Cholesterol curcumin release at pH to 395.55 ± 84.92 ± 0.57 Shivakumar, and
7.4, in vivo formulation 3.2 Ojha (2019)
skin penetration
Liposome: Soy Phosphatidylcholine & Sea Fennel Aqueous Characterization, EE%, Freeze-Dried 89.5 to 137.1 65.6 and 49.1 for Alemán, Marín,
Cholesterol & Ethanolic Extract The liposomal & 96.3 to aqueous and Taladrid, Montero,
antioxidant activity & 150.1 ethanolic extract, and Carmen
Total phenolic content respectively Gómez-Guillén
(2019)
Liposome: Sunflower Lecithin Curcumin, Impact of pH, Solubility High- Pressure – 100, 54 & 93 Peng, Zou, et al.
(Sunlipon 65) & Cholesterol Quercetin, & & Chemical stability, EE Homogenization (2019)
Resveratrol %,

4.3. Carbohydrate-based delivery systems
Carbohydrates consist of polysaccharide, oligosaccharide and
monosaccharide are natural biocompatible, bioavailable, the suitable
shell under high temperature process, inexpensive food ingredients, and
biodegradable materials, which can interact with different kinds of
bioactive compounds via their functional groups, thus entrapping wide
varieties of hydrophilic and hydrophobic bioactive compounds’ in­
gredients (Kim, Lee, & Lee, IN PRESS). Therefore, different kinds of
carbohydrates and their combinations or chemically modified forms
have been applied for assembling nanodelivery systems, including cel­
lulose, chitosan, alginate, native gums, cyclodextrins, pectin, guar gum,
dextrin, and starch. In addition, they can be used as a suitable shell for
the encapsulation of drugs or nutraceuticals due to their
high-temperature stability in comparison with lipid or protein-based
delivery systems due to the possibility of their denaturation or
melting. They are classified by their isolation methods, physical,
chemical, or biochemical modifications, and biological origins including
plant (e.g. pectin, cellulose, starch, and guar gum), animal (e.g. chito­
san), microbial (e.g. xanthan, cyclodextrins, and dextran), and algal
origin (e.g. carrageenan and alginate). Also, different methods including
coacervation, electrospinning, electrospray, supercritical fluid, spray
drying, emulsion-diffusion, emulsion-droplet coalescence, reverse
micelle, emulsification/solvent evaporation, salting out, high-pressure
homogenization, and ultra-sonication are applied for assembling
carbohydrate-based nanocarriers (Assadpour & Jafari, 2019).
Natural starch is the famous polysaccharide in plants, consisting of
glucose units linked to α-d-(1 → 4) and/or α-d-(1 → 6) linkages, which is

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Table 3
Overview of Bioactive Compounds Encapsulated by Carbohydrate- Based delivery systems.
Encapsulating Materials Nutraceutical Study/Target Encapsulation Size (nm) Encapsulation References
Technique Efficiency (%)

Quinoa & maize starch NPs Rutin Characterization, EE%, Simulated in Ultrasonication 107 and 222 67.4 & 26.6 Remanan and Zhu
vitro digestion (2021)
Chitosan NPs: Chitosan, & Red Ginseng Extract Antithrombotic activities, Ex-vivo & Ionic Gelation 286 ± 36.6 20.78 ± 0.20 Kim et al. (IN PRESS)
TPP Solution In vivo antiplatelet activities, In vivo
carrageenan-induced mouse tail,
Arteriovenous shunt rat thrombosis
models
Gum Arabic (GA)-based Probiotic: Viability of GA/PUL-encapsulated Electrospinning 283.15 ± – Ma et al. (2020)
nanofibers in combination Lactobacillus Lactobacillus & Storage stability 68.44 to
with Pullulan 61.05 ±
16.67
Chitosan/Gum Arabic The Antioxidant In vitro digestion, EE% Ionic Gelation CSGA: 273.2 41 to 45.3 Jeong, Lee, and Lee
(CSGA) & Chitosan/ Combination ± 23.3 to (2019)
Carrageenan (CSCR) NPs (Blueberry & 327.2 ± 23.8
Cabbage CSCR: 194.8
Concentrates) ± 14.9 to
468.9 ± 42.0
Azivash (Corchorus olitorius. Catechin Simulated gastric fluid & Simulated Electrospinning 500–1000 98.98–84.48 Hoseyni et al. (2021)
L) gum-polyvinyl alcohol intestinal fluid, EE% Process
Maltodextrein NPs Green Coffee Characterization NPs, In vitro Spray Drying 40-70desai 82.34 Desai et al. (2020)
bioactivity of NPS, Storage stability
Chitosan NPs: Chitosan, & Curcumin Oral bioavailability/Antiviral Complexation 332.4 ± 9.4 77.2 ± 3.6 Ng et al. (2020)
TPP Solution effects, Cytotoxicity effect on
Crandell-Rees feline kidney (CrFK)
cells
Nanoparticles: chitosan (CS) Saffron Bioactive Characterization NPs, EE%, Release Ionic Gelation 183–295 29.12 to 52.34 Rajabi, Jafari,
& Gum Arabic (GA) Components of Saffron in acidic and natural (IG) Rajabzadeh, Sarfarazi,
media and Sedaghati (2020)
Nanofibers: Poly (ethylene Aloe Vera skin Thermal stability & antioxidant Electrospinning 185 ± 25 to 76–105 Solaberrieta, Jiménez,
oxide) solutions/Mucilage extract activity, EE%, 250 ± 30 Cacciotti, and
Nanofibers Garrigós (2020)
Nanofibers: Basil Seed Hesperetin (HSP) Characterization of nanofibers, Electrospinning 82–320 89–96 Kurd, Fathi, and
Mucilage/ Release models, EE% Shekarchizadeh
Polyvinylalcohol (2019)
Chitosan NPs: Chitosan, & Java Tea Anti-hyperglycemic, Spray Dryer 217.7 – Naibaho, Safithri, and
TPP Solution (Orthosiphon Malondialdehyde level analysis in Wijaya (2019)
Aristatus BlMiq) vitro
Nanoparticles: Sodium Clove Essential Oil EE%, Antimicrobial Assessment, in Homogenization – 83.60–92.2 Radünz et al. (2019)
Alginate, Glycerol vitro inhibitory & bactericidal
Monostearate or Poly activity
Oxyethylene Sorbitan
Monolaurate
Chitosan NPs: Chitosan, & Physalis Alkekengi-L Antioxidant capacity & Anticancer Ionic Gelation 196 ± 20 95 ± 3.2 Mahmoudi et al.
TPP Solution Extract activity, EE% (2019)
Maltodextrin NPs Grape Pomace The effect of NPs/GPE on Spray Dryer – 82.81 ± 1.15 Dordoni et al. (2019)
Extract (GPE) antioxidant properties & Sensory
acceptability of whole wheat cocoa
biscuits, EE%
Starch NPs Catechin Hydrate Characterization of NPs, Release in Sonication & 322.7, 559.2 59.09, 48.30, & Ahmad et al. (2019)
simulated in vitro digestion, EE% Freeze Dryer & 615.6 55.00
NPs: Balangu (Lallemantia Mentha Longifolia L. Increase their utility as flavoring and Electrospray 96.53 ± 3.41 81.54–87.82 Rezaeinia, Ghorani,
Royleana) Seed Gum Essential Oil bioactive agents in foods and Emadzadeh, and
Nanocapsules (Balangu beverages, Release models, EE% Tucker (2019)
Seed Gum & Polyvinyl
Alcohol

biodegradable, digestible polymer and biocompatible, consist of
amylose and amylopectin and is hydrophilic, which limits its application
for hydrophobic nutraceuticals but its hydrophobic derivatives such as
dialdehyde starch and propyl starch developed for encapsulation of
lipophilic bioactive compounds. The main limitation of starch for
encapsulation of bioactive compounds is its sensitivity to acid media and
amylase hydrolysis. Cellulose is another abundant polysaccharide
composed of glucose linked with β-d (1 → 4) linkages, which has low-
water solubility and large dimensions but using cellulose-based nano­
carriers due to their non-digestible by the colon or microbial enzymes
should be taken into account for their absorption and potential toxic
impacts (Assadpour & Jafari, 2019).
Pectin as a linear anionic polysaccharide consists of linearly
connected α-d-(1 → 4) galacturonic acid residues, which is resistant to
enzymatic degradation in the stomach and mouth but it is digestible by
the microflora and can be suitable for delivery of the acid-sensitive food
(Assadpour & Jafari, 2019).
Guar gum is derived from seeds of Cyamopsis tetragonolobus and is
water-soluble consists of linear chains of β-d-(1 → 4) mannopyranosyl
units with α-d-galactopyranosyl units connected by (1 → 6) linkages
which is resistant to enzymatic degradation in the small intestine,
stomach and mouth and degrades in the colon. Its highly viscous solu­
tions limit its usage which its modification should be considered. Also,
poor hydration and low thermal stability are other limitations of using
guar gum as nanocarriers (Ng, Selvarajah, Hussein, Yeap, & Omar,
2020).

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L. Rashidi
Chitosan is a biodegradable, cationic, and biocompatible polymer
which is obtained from alkaline deacetylation of chitin, has antimicro­
bial and antioxidant activities, possible prolonging resistance time,
possibility of physical or chemical modifications to extend biopolymer
functional characteristics and enhancing sustained release in gastroin­
testinal media. Alginate is obtained from brown sea algae and consists of
alternating blocks of 1 → 4 connected to β-D-mannuronic acid and α-L-
guluronic which can be applied for encapsulation of hydrophilic
bioactive compounds (Ng et al., 2020). Dextran consists of chains of
glucose α-(1 → 6) and the small amount of α-(1 → 3) linkages containing
hydroxyl groups, which can be applied for the covalent attachment of
different organic functional groups. It can be applied for encapsulation
of bioactive compounds with various hydrophobicities (Desai, Stanley,
& Murthy, 2020). Cyclodextrins consist of 6, 7, or 8 (α, β or γ-CDs)
glucose units liked by α-(1 → 4) glucoside bonds, which central cavity is
hydrophobic and the external surface is hydrophilic. CDs can be useful
for the encapsulation of temperature-sensitive, poorly soluble and
chemically labile bioactive compounds (Desai et al., 2020)..
Table 3 presents an overview of bioactive agents or nutraceuticals
encapsulated by carbohydrate-based nanocarriers.
4.4. Nanocomplexation
The complexation method is a proper nanoencapsulation system for
the conservation of bioactive food ingredients or nutraceuticals, which
traps the core materials in an assembly of two biopolymers (Desai et al.,
2020). Generally, biopolymers are organized by linking proteins and
polysaccharides through electrostatic absorptions that contain better
chemical and colloidal conservation. Therefore, the net positive charge
of protein interplays with the anionic groups upon the polysaccharide at
pH values less than the protein’s isoelectric point (pI). The biopolymer
complexation is commenced using the layer-by-layer method by the
adsorption of ionic polysaccharides onto pre-organized protein nano­
particles (Rajabi et al., 2020). The stability of nanocomplexation carriers
depends on several factors, including ionic strength, pH value, confor­
mation, charge density, the ratio of the biopolymers, and the concen­
tration of both polysaccharides and proteins (Okagu, Verma,
McClements, & Udenigwe, 2020). Moreover, the complexation of car­
bohydrates or proteins with the phenol compounds has widely been
studied for improved stability and delivery of those compounds,
particularly those with low solubility and bioavailability. Advantages of
using these complexes include the biodegradability, lower toxicity, and
biocompatibility with cells. In recent years, numerous studies were
conducted for the encapsulation of nutraceuticals, including ferulic acid
by the complexes of maltodextrin (FA/MD) and hydroxypropyl
Table 4
Overview of bioactive compounds encapsulated by polymer-based delivery systems.
Encapsulating material Nutraceutical Study/Target
PEGylated poly (lactide-co- Sophorolipid In vitro & In vivo model
glycolide), Resomer® RGPd tumor cell lines (CT26
50,105 NPs murine colon carcinoma) &
the effect of peripheral
hydrophilicity
Poly (lactic-co-glycolic acid) 3, 3′ -Diindolylmethane Cytotoxicity effect on
(PLGA) & Poly (ethylene (DIM) & Ellagic Acid pancreatic cancer cell
glycol) (PEG) [PLGA-PEG] (EA) (suit2) implant model
NPs
Poly (lactic-co-glycolic acid) Callistemon Citrinus & Cytotoxicity effects on
NPs Berberine Extract MDA-MB231, MCF-10 A,
MCF-7breast cancers
Curcuminoids NPs: Curcuminoids In vitro modulation
(Polyvinylpyrrolidone (PVP)) Extracted From capacity on the enzymes,
Curcuma Longa L. Cytotoxicity effect on tumor
& non-tumor cells
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Food Bioscience 43 (2021) 101258
methylcellulose (FA/HPMC) using spray drying method, and encapsu­
lation efficiency percent (EE%) 80.12 ± 1.57, and 85.56 ± 6.01 (Yu,
Roh, & Park, 2021); curcumin by a complex of an insect protein as
mealworm protein and chitosan (particle size: 143–178 nm) using ho­
mogenization followed by freeze dried methods and 30 to 47 EE%
(Okagu et al., 2020); curcumin by a complex of ovalbumin (OVA) and
sodium alginate (particle size: 300–330 nm) using the homogenization
technique with 70–80 EE% (Feng et al., 2019); Epigallocatechin gallate
by a complex of piperine into a zein nanocarrier (particle size: 34.03 ±
3.1 nm to 83.49 ± 7.2 nm) using anti-solvent precipitation technique
(Dahiya, Rani, Dhingra, Kumar, & Dilbaghi, 2018); folic acid by a
complex of 7 S and 11 S globulins and folic acid (FA) using the
complexation technique (particle size: 19.57 ± 1.2 to 51.33 ± 1.3 nm)
(Ochnio et al., 2018).
5. Non-food grade delivery systems
5.1. Polymeric nanocarriers
Polymeric carriers (including poly (D, L-lactide), poly (lactic acid),
PLA, poly (D, L-glycolide), PLG, poly (lactide-co-glycolide), PLGA, and
poly (cyanoacrylate), PCA) can be used to entrap both hydrophilic and
hydrophobic nutraceuticals. They should have proper biocompatibility,
biodegradability, mechanical strength, The Food and Drug Administra­
tion (FDA), 2014 (FDA) approval, and low synthesis complexity. The
poly (lactic-co-glycolic acid) (PLGA) which is a copolymer of the poly
(lactic acid) (PLA) and poly (glycolic acid) (PGA) is the most attractive
one (Zorkina et al., 2020). Nanocarriers based on polymeric micelles
have certain advantages, including low toxicity, small size, potential
application for the treatment of various cancers, greater mechanical and
chemical stability, biocompatibility, ease of production, sustained
release of nutraceuticals, ease of modification, and increase of repro­
ducibility. Also, polymeric nanoparticles as the drug or bioactive agent
delivery system can be used for the localized or targeted delivery sys­
tems of a drug or nutraceutical to specific tissues or organ sites with an
optimal release rate (Zorkina et al., 2020). They are synthesized by
different techniques, including solvent evaporation, salting out, dialysis,
and supercritical fluids. Disadvantages of synthetic polymers are the
possibility of their uncertain potential toxicity and some of them are
non-degradable or have slow degradability, coupled with a complex and
costly production of them. In addition, the efficiency delivering of
nutraceuticals by polymeric micelles across the intact BBB still needs
more investigation. Table 4 presents the nutraceuticals encapsulated by
polymeric nanocarriers (Zorkina et al., 2020).
Encapsulation Size (nm) Encapsulation References
technique efficiency (%)
Nanoprecipitation PLGA: 196.5 ± 68.8 ± 6 in PLGA to (Haggag et al.,
20.9117.5 ± 92.18 % ± 1.8 % in 2020)
11.5 in 10 % 10 % PEG-PLGA
PEG-PLGA
Double Emulsion/ 180–210 80 (Mousa, El-Far,
Solvent Evaporation Saddiq, Sudha,
& Mousa, 2020)
Nanoprecipitation 200–250 80 (Ahmed et al.,
2019)
Nanoprecipitation Smaller than – (Santos et al.,
450 2019)
L. Rashidi Food Bioscience 43 (2021) 101258

Table 5
Overview of bioactive compounds encapsulated by silica –based delivery systems.
Encapsulating materials Nutraceutical Study/Target Size (nm) Encapsulation References
efficiency (%)

Pegylated lipid bilayer coated MSNs Curcumin Characterization of NPs, 115 ± 15 30.70 ± 3.56 Lin et al. (2018)
Cytotoxicity effect on CHO
FA-MSN-N–
–C (folic acid conjugated to Curcumin Stability under physiological 136 ± 4 to 165 49.6 ± 1.9 Chen, Sun, Wang, Wang, and
MSN-NH2) conditions, internalization into ±4 Wang (2018)
MCF-7 cells, & HEK-293 T
normal cell
Polyethyleneimine coated MCM-41 Curcumin Characterization of mcm-41, 100–200 – (Harini et al., 2017)
Anticancer property on MCF-7
cells, Release of curcumin at pH
3
MCM-48 particles Resveratrol Cytotoxicity effect on human 90, 150 & 300 – Juère et al. (2017)
colon carcinoma cell
monolayer (Caco-2), Anti-
inflammatory
Carboxyl Group-MSNs (PSNs-C) Vitamin B12 & Cisplatin Characterization of PSNs-C, 316 ± 6 – Thepphankulngarm,
Release at pH 5.5 Wonganan, Sapcharoenkun,
Tuntulani, and Leeladee
(2017)
Amino Functionalized MSNs Vitamin E (VE) characterization of MSNs, LMSN:282 VE@NH2-MSN: Zhuoxian et al. (2017)
LMSN,NH2-LMSN & VE@NH2-LMSN Release at pH 7.4, In vitro cell NH2-LMSN: 325 37.7 ± 2.5
tests and hemolytic
experiments
Fluorescein isothiocyanate-dyed MSNs Gallic acid Characterization of MSNs, 100 ± 10 for – (Rashidi et al., 2017)
(FITC-MSNs) and its Functionalized by cytotoxicity effect on Caco-2 FITC-MSNs &
3-Aminopropyltriethoxysilane (APTES) cells 130 ± 15 for AP-
(APFITC-MSNs] FITC-MSNs
MCM-41 (TMABr as surfactant and sodium α-Tocopherol Characterization of MCM-41, – – (Sun, Lu, Qiua, & Tang,
silicate) tensile strength, oxygen and 2017)
water barrier properties,
Antioxidant activity
Colloidal MSNs (MCM-48) Resveratrol (RES) saturated solubility of RES, 191 & 283 – (Summerlin et al., 2016)
cytotoxicity effects on HT-29 &
LS147T colon cancer cell lines,
anti-inflammatory on
RAW264.7 cells
Mesoporous silica nanoparticles (MSNs) Curcumin & Chrysin characterization of NPs, Curcumin: Curcumin & (Lungare, Hallam, &
cytotoxicity effect on olfactory 216.8 ± 2.1 to Chrysin: 12.34 ± Badhan, 2016)
neuroblastoma cells OBGF400 263.51 ± 8.3 1.28
Chrysin: 216.8
± 2.1 to 283.5 ±
8.3
MSNPs, AMSNPs and AMSNPs-MO, 3- Morin (2 ́ ,3,4 ́ ,5,7- Characterization of NPs, MSNP: 105 – (Arriagada et al., 2016)
Aminopropyltriethoxysilane (APTES) pentahydroxyflavone) adsorption kinetics, Isotherm & AMSNPs: 125,
Antioxidant capacity AMSNPs-MOR:
155
MCM-41nanoparticles Folic acid (FA), vitamin Characterization of NPs, pH 250–300 – Popescu et al. (2016)
MCM-41/Fe3O4 dependent release
Mesoporous-silica-coated up conversion Vitamin B12 Characterization of NPs, 100 – Xu, Ding, et al. (2016)
nanoparticles Release behavior in different
pH
Lipid bilayer coated-curcumin loaded Curcumin Characterization of NPs, 200 – (Datz, Engelke, Schirnding,
colloidal periodic mesoporous Cytotoxicity effect on Hela cells Nguyen, & Bein, 2016)
organosilica nanoparticles
Self-Fluorescent & Stimuli-Responsive Curcumin Characterization of NPs, 117 – Xu, Lü, et al. (2016)
MSNs Release behavior in different
pHs 7.4 & 5.5,
Silica-based mesoporous materials (MSU- Curcumin Charcterization of NPs, 5.9–38 – Bollu et al. (2016)
2 & MCM-41) cytotoxicity effect on CHO &
MCF-7, A549, Release at pH 7
The outer of the MSN decorated with poly Topotecan (TPT) & Charcterization of NPs, 65–75 TPT: 1.8 (Murugan et al., 2016)
(acrylic acid)-chitosan, grafting of Quercetin (QT) Cytotoxicity & ROS generation QT: 1.2
arginine-glycine-aspartic acid effect on MDA-MB-231 & MCF-
7, A549, Release at pH 7.4

5.2. Mesoporous silica nanoparticles
Mesoporous silica nanoparticles (MSNs) are suitable nanocarriers for
drugs and bioactive compounds due to their unique properties,
including surface functionality, good biocompatibility, stability, high
drug loading capacity, sustained release and targeted delivery of a va­
riety of drug molecules, unique the mesoporous structure and chemical
resistance of the structure. They have a honeycomb-like structure and
active surface which could be functionalized to modify surface proper­
ties and link drug or bioactive molecules. MSNs can be synthesized by
sol-gel or spray drying methods and applied for loading and targeted
delivery of hydrophobic, hydrophilic, and negatively or positively
charged drugs or bioactive compounds (Rashidi, Ganji, &
Vasheghani-Farahani, 2017). MSNs have been applied in a wide variety
of industries, including feed, cosmetics, and pharmaceutical products,
for many decades. Based on extensive physicochemical, ecotoxicology,

11
L. Rashidi
toxicology, safety, and epidemiology data, no environmental or health
risks have been associated with these materials. They do not exert any
toxicological effects on medicines, and are approved to be GRAS
(Rashidi et al., 2017). The limitations of these nanocarriers include
potential toxicity in high concentrations, contribution to the level in­
crease of reactive species, and inducing the elevated malondialdehyde,
and decreasing glutathione level (Zorkina et al., 2020). Table 5 indicates
an overview of nutraceuticals encapsulated by mesoporous silica
nanoparticle carries.
5.3. Mesoporous silica nanoparticles
Magnetic nanoparticles (MNPs) possess general characteristics of
nanoparticles and magnetic properties. These nanostructures are
considered as particles with the size of lower than 100 nm, which their
magnetic properties are determined by many factors such as the degree
of deficiency of the crystal network, the morphology, the chemical
composition, the interplay of the particle with the neighboring matrix,
the type, and the particle shape and size, and the adjacent particles. The
great properties of MNPs are including excellent reactivity, larger
surface-to-volume ratio, and unique magnetic response compared to
their bulk materials (Hajba & Guttman, 2016). These nanoparticles are
mainly categorized to the metal nanoparticles (Fe, Co, Ni, etc.), metal
oxide (Fe3O4, γ-Fe2O3, CoFe2O4, etc.), and metal alloy nanoparticles
(FeCo, alnico, permalloy, etc.). The common nanoparticles are iron,
cobalt, silver, gold, and nickel. Metal nanoparticles have a higher
saturation magnetization but they are toxic and not suitable for drug/­
gene delivery or clinical use (Vittorio et al., 2014), therefore, they are
coated using natural materials. There are different methods for synthe­
sizing these nanoparticles, including deposition method,
co-precipitation, microemulsion, thermal decomposition, ball milling,
polyol, spray pyrolysis, and hydrothermal or solvothermal. Nowadays,
several studies have been reported the application of MNPs as the car­
riers for the delivery of polyphenols in order to the treatment of tumors.
These carriers are easily biodegradable, nontoxic, and have chemical
stability in physiological situations, and possibility of chemical modifi­
cation using the coating of magnetic nanoparticles but these nano­
carriers tend to aggregate into larger clusters and potentially toxic in
high concentrations. In a study carboxymethyl cellulose -Magnetic
nanoparticles applied for encapsulation of galbanic acid using precipi­
tation method for studding its cytotoxicity effect on Prostate Cancer
Cells which particle size and encapsulation efficiency were obtained
9.39 nm and 40.36 %, respectively (Mohtashami, Ghows,
Tayarani-Najaran, & Iranshahi, 2019). Also, Iron oxide, silica-coated
iron oxide (SIOMNPs), chitosan-coated iron oxide (CIOMNPs) were
synthesize by alkaline hydrolysis technique for encapsulation of cellu­
lase with particle sizes (45–60, 80–150 & 30–50 nm) and encapsulation
efficiencies (82, 97, & 67 %) (Kumar et al., 2019). Magnetic nano­
particles coated by dextran were synthesized for encapsulation of cate­
chin by precipitation method and used for investigating its therapeutic
effect for pancreatic tumor cells with the particles size of 91 nm (Vittorio
et al., 2014).
5.4. Carbon nanotubes
The carbon nanotube is similar to a graphite sheet rolled into a
carbon cylinder composed of the benzene ring with specific hexagonal
latticework that constitute the sheet. These nanostructures have been
used in biology as sensors for detection of DNA and protein, or as
diagnostic devices for distinction of various proteins from serum sam­
ples, and also as carriers to deliver vaccine, polyphenol, protein, or drug
(Kumari, Singla, Guliani, & Yadav, 2014). There are two main kinds of
CNTs, including single-walled nanotubes (SWCNTs) composed of a sin­
gle graphite sheet seamlessly wrapped into the cylindrical tube and
multi-walled nanotubes (MWCNTs) consist of the array of nanotubes one
concentrically located inside another like rings of a tree trunk. Various
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Food Bioscience 43 (2021) 101258
methods are reported for the formation of carbon nanotubes including
arc discharge, carbon monoxide disproportionation, laser ablation,
chemical vapor deposition (CVD), and hydrothermal method (Kumari
et al., 2014). The advantages of carbon nanotubes are low-cost, high
aspect ratios, biocompatibility, surface area, high thermal and electrical
conductivity, light-weight, distinct optical characteristics, efficient
loading of multiple molecules and high mechanical strength. Carbon
nanotubes are part of the fullerene family which fullerenes are made up
of graphene sheets of linked pentagonal and hexagonal rings leading to
them their curved structure (Kumari et al., 2014). Limitations of using
carbon nanotubes include potential toxicity, similarity in carcinogenic
potential between carbon nanotubes and asbestos, cannot be function­
ally integrated into the biological systems unless surface functionaliza­
tion, enable cause necrosis or apoptosis of macrophage cell lines and
modifies cell morphology and contribute to the level increase of reactive
oxygen species. A single-walled carbon nanotube (SWCNT) embedded in
a 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) lipid bilayer con­
taining curcumin was synthesized by layer-by-layer technique with
particle size of 2.12–2.7 (Sahoo, Kanchi, Mandal, Dasgupta, & Maiti,
2018). The biocompatible nanotubes constituted of Poly-d-lysine (PDL)
and BSA and, Polycarbonate (Bio nanotube (BNTs)) were prepared for
encapsulation of curcumin as a bioactive model using layer-by-layer
which the particle size was 400 nm and encapsulation efficiency was
obtained 45 % (Sadeghi et al., 2013).
5.5. Dendrimers
A dendrimer is a macromolecule, monodispersive, highly branched,
spherical and symmetric. The dendrimer structure is three-dimensional
highly branched, and also radially symmetrical. The dendrimer core is
available for the encapsulation of drugs, bioactive agents, or nutra­
ceuticals and the peripheral functional groups are accessible for the
modification of nutraceutical molecules through covalent bonds and for
the formation of the complex. Dendrimers are generally synthesized
using the divergent method or the convergent one, in which the den­
drimer grows external from the multifunctional core molecule. The core
molecule of dendrimer reacts with monomer molecules owning two
dormant groups, and one reactive which giving the first-generation
dendrimer (Abbasi et al., 2014). The merits of using these nano­
carriers are the situation of core is suitable for entrapping bioactive
compounds, the existence of numerous surface groups lead to increase
loading percentage of nutraceuticals, and potential conjugation of sur­
face groups with target ligands, but its demerit is potential toxicity.
Curcumin encapsulated in Polyamidoamine (PAMAM)
dendrimer-plamitic acid core-shell nanoparticles were prepared by hy­
drophobic and hydrophilic interaction via hydrogen bonding and par­
ticle size and encapsulation efficiency were 257.9 nm and 80.8 %,
respectively (Tripathi et al., 2020). PAMAM G4 dendrimers conjugated
PEG were synthesized for encapsulation of curcumin via hydrogen
bonding method which the particle size and encapsulation efficiency
were 506.3–547.8 nm and 69.81–90.5%, respectively (Elfiyani, Srifiana,
& Al Rasyied, 2018). Also, PAMAM dendrimers were prepared for
encapsulation of resveratrol, genistein and curcumin by hydrophobic
and hydrophilic interaction via hydrogen bonding with the particle size
of 10 nm and encapsulation efficiency of 30–55 % (Chanphai &
Tajmir-Riahi, 2016). In addition, PAMAM dendrimers were prepared for
encapsulation of berberine (BBR) by hydrophobic and hydrophilic
interaction via hydrogen bonding with the particle size of 100–200 nm
and encapsulation efficiency 29.9–37.5 % (Gupta et al., 2017). In
another study, PAMAM dendrimers were synthesized for encapsulation
of quercetin by hydrophobic and hydrophilic interaction via hydrogen
bonding with a particle size lower than 100 nm (Madaan, Lather, &
Pandita, 2016).
L. Rashidi
6. Safety issues of using nanomaterials in the food industry
Recently, the increased application of nanotechnology and the high
number of its derived commercial applications has led to concerns
regarding their potential risk for human health. Some reports are
focusing on the evaluation of nanocarriers’ or nanomaterials’ toxicity
when they form part of a food matrix. Materials at the nanoscale can
easily penetrate and accumulate within the human body, sub-cellular
boundaries, and breaching the cellular walls, which have an unpre­
dictable impact on the human body, plants, animals, and the environ­
ment because of potential toxic effects (Yu et al., 2018). The safety of
nanomaterials and their hazards of using them remain unexamined, and
require a main risk assessment. The study of direct and indirect impacts
of nanomaterials on human health, including the biological fate of
nanomaterials after digestion and their behavior within the gastroin­
testinal tract (GIT), and also their possible interactions with biological
systems must be studied. Moreover, it is essential to develop regulatory
controls for the protection of public health from potentially adverse
effects of nanomaterials (Yu et al., 2018). Several expert bodies are
active in this domain, including the International Standard Organization
(ISO), the US Food and Drug Administration (FDA), the Organization for
Economic Cooperation and Development (OECD), and EU Scientific
Committees and Agencies. In addition, the scientific opinion as a
guideline for the nanoscience and nanotechnology risk evaluation in
feed/food applications has been published by the European Food Safety
Authority, 2021 (EFSA, 2021). In the EFSA, nanoparticles are defined as
engineered nanomaterials (ENMs) which have a minimum of one
dimension within the range of 1–100 nm. If these nanomaterials are
present in a food product, they must go through a precise risk evaluation
to prove that they are not hazardous for human consumption. Also, the
US FDA published a draft guideline for using nanomaterials in animal
feed (The Food and Drug Administration (FDA), 2014). A recent EU
legislation (No. 1169/2011) has necessitated the labeling of nano­
materials on the packaging of novel foods (European Parliament, 2011).
By observing modern food regulations and any new nanotechnology
regulation for providing the public with information, the safety of
nanomaterials in the food and feed industry can be ensured. Nowadays,
there are many bioactive compounds encapsulated into nano-delivery
systems which are commercially available in the market, including
Nanotea (company Qinhuangdao Taiji Ring Nano), OilFresh (company:
OIlFresh corporation, USA), LifePak and NanoCoQ10 (company: Phar­
manex), Nano C (company: Neurvana), Nano Resveratrol and Nano
Curcumin (company: Neurvana), ACZnano Advanced Cellular (com­
pany: Vitality Products, USA).
7. Conclusions
Considerable attention has been paid to the development of nano-
scale delivery systems for the protection of nutraceuticals against un­
balanced and unfavorable conditions. In addition, the functional food
market developed over the decades because of increasing consumer
demand for nutraceuticals, nutritional and healthy food products. Also,
there are numerous demands for reducing the amounts of applying
synthetic preservatives and ingredients in the food industry. In this re­
view, different nano-delivery systems employed for the protection and
delivery of nutraceuticals were investigated. Based on the researches,
non-food grade delivery systems possess more stability than food grade
delivery systems but some of them are toxic in high concentrations
which sometimes for reduction of toxicity, their surface should be
functionalized by nontoxic material. It is necessary to characterize the
distribution, absorption, elimination, and metabolism behavior of nano-
delivery systems carrying the bioactive agents or nutraceuticals in order
to potentiate therapeutic applications and increase the efficacy of
nutraceuticals in functional foods. In the future, it is important to
determine the acceptable daily intakes of the nanoencapsulated nutra­
ceuticals and to evaluate the safety of nano-delivery systems for suitable
13
Food Bioscience 43 (2021) 101258
applications in the food industry. This should be conducted by proper in
vivo models, which will lead to the establishment of legal regulations to
defend consumers safety in which industry and society can receive
benefit from new nanotechnology applications in food production,
defending the safety, the environment and the health. In addition,
further research should be conducted for the development of nano-
delivery systems that are commercially viable.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
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