Nanodelivery of Food Polyphenols for Nutraceutical Applications

Full text

312
Polyphenols: Food, Nutraceutical, and Nanotherapeutic Applications, First Edition. Edited by Mithun Rudrapal.
© 2024 John Wiley & Sons, Inc. Published 2024 by John Wiley & Sons, Inc.
15
Nanodelivery of Food Polyphenols for Nutraceutical Applications
Aamena Yusuf1, Tanisha Ambawat1, Sneha Dokhale2, Shine Devarajan1, and
Samiksha Garse1,*
1 School of Biotechnology and Bioinformatics, D Y Patil Deemed to be University, Navi Mumbai, Maharashtra, India.
2 B. K. Birla College, Birla College Campus Rd, Kalyan, Maharashtra, India.
* Corresponding author
15.1 Introduction
Polyphenols are plant-based, non-nutrient natural components also termed as secondary metab-
olites. These are included in plant-based daily diets [1]. The substances are generated through
the shikimate/phenylpropanoid and/or polyketide pathways that have several phenolic units
but no nitrogen-based functionalities are referred to as polyphenols [2]. Most plants naturally
contain polyphenols, which have a complex and unique chemical structure resulting in a wide
range of biological properties [3, 4]. According to epidemiological studies and meta-analyses,
consuming diets high in plant polyphenols over the long term may provide some protection
against the advancement of neurological diseases, diabetes, osteoporosis, and cardiovascular
diseases, as shown in Figure 15.1 [3].
Many polyphenolic substances have limited oral bioavailability, which constrains their use in
nutraceuticals. Green bio-based nanocarriers are ideal for encapsulating, storing, and packing
polyphenols, thus enhancing their bioavailability [2, 4, 5].
In a variety of sectors, bio-based polymers have arisen as a viable alternative to petroleum-
based polymers [6]. Proteins are versatile bio-based polymers with different functional qualities
such as emulsification, amphiphilicity, gelation, and foaming [7]. Polysaccharides are also bio-
based polymers with a diverse variety of origins, and their distinctive structure and physiologi-
cal activity make them suitable as ingredients for the creation of a variety of nanocarriers and
the transport of polyphenolic chemicals [8]. Lipid-based nanocarriers are also some of the most
important methods for targeting such transportation in food and nutrition due to their excel-
lent biocompatibility and biodegradability [9]. The introduction of several marketed modified
polyphenol products sets the groundwork for additional study and development of novel poly-
phenol health nutrition products [5]. The label “Nutraceutical” was a blend of “Nutrition” and
“Pharmaceutical”, by Dr. Stephen DeFelice [10]. The definition of a nutraceutical given by
DeFelice is “a food (or part of a food) that provides medical or health benefits, including disease

15.2 Polyphenols: Classification, Health Benefits, Bioavailability 313
prevention and treatment” [11]. Any food-sourced
product that offers notable wellness advantages in
addition to the essential nutritional content
included in meals is referred to as a nutraceutical.
Nutraceuticals are grouped into four major catego-
ries, as shown in Figure 15.2.
Hippocrates once said, “Let food be your medi-
cine”; this is the fundamental tenet of nutraceuti-
cals. Nutraceuticals signaled a new age in food
health and medicine, as people become more mind-
ful of the relationship between critical illnesses and
eating behavior [11]. Natural honey is one of the
best nutraceutical products because it contains
antioxidants and enzymes that are necessary for
digestion [12]. Because of their potential to increase
bioavailability, component solubility, and stability,
these have been widely employed in nanotechnol-
ogy [13]. Nanotechnology is enhancing the whole
industry of food, from production to processing,
storage, and consumption. Nanoparticles (NPs) for
edible delivery are physiologically consistent small
materials ranging in size from 1 nm to 100 nm and
they are generated using various ways that produce
important physio-chemical properties. These fea-
tures of NPs make them useful in an array of
domains [13]. This chapter discusses the nanodeliv-
ery of food polyphenols for nutraceuticals with
improved solubility, bioavailability, efficiency,
encapsulation, and prolonged and focused drug
delivery.
15.2 Polyphenols: Classification, Health Benefits, Bioavailability
Polyphenols are phenolic hydroxyl group-containing organic molecules that are found abundantly
in natural flora. They have been shown to benefit human health immensely because of their anti-
oxidant properties, adherence affinity, and anticancer properties. They also show great promise in
the bioimaging, biomedical, and therapeutic industry by the preparation and modification of
nanoassemblies [4, 14]. These compounds, which are classified as phenolic acids, flavonoids,
anthocyanins, and tannins, possess complicated structures, and use phenolic rings as their core
monomer. Polyphenols from tea and coffee are bioavailable; approximately 30% of these com-
pounds are absorbed in circulation in humans, and regular consumption of these compounds
results in improvements in biomarkers for oxidative stress [4, 14, 15]. Grosso revealed that 75% of
polyphenols come from beverage and chocolate consumption in a population-specific analysis
within Poland [16].
Figure 15.1 Health benefits of polyphenols.
Figure 15.2 Classification of nutraceuticals.

15 Nanodelivery of Food Polyphenols for Nutraceutical Applications
314
15.2.1 Classification of Polyphenols
Food polyphenols are a diverse group of organic substances from the kingdom Plantae, the major-
ity of which have two phenyl rings and one or more hydroxyl groups [17]. The classification of the
same is given in Figure 15.3. There are currently 8,000 polyphenolic chemicals known, and more
than 4,000 of them are flavonoids [18]. Flavonoids and phenolic acids are the two main classes of
the diverse collection of phenolic chemicals known as polyphenols; phenolic acids are split into
two types, hydroxycinnamic and hydroxybenzoic acids. Flavonoids are colored chemicals that are
further divided into flavones, flavanols, flavanones, flavonols, and isoflavones [19]. They can be
found either unconjugated (as an aglycone) or conjugated with substances, including lipids, glu-
cose, carboxylic acid, amines, and organic acids. Polyphenols are divided into phenolic acids,
phenolic aldehydes (vanillin, salicylaldehyde, syringaldehyde, etc.), flavonoids, iso-flavonoids,
tannins (hydrolyzable and condensed tannins), lignans, and lignins based on the structural vari-
ation [20, 21].
Dietary polyphenols exhibit a wide variety of structural types, from straightforward compounds
like monomers and oligomers, to complex polymers with high densities. High-molecular-weight
(>500) structures are referred to as tannins because of their capacity to interact with proteins.
Condensed tannins stand out among their contribution to food quality and widespread occurrence
in flora [18].
However, because of their extremely unstable nature, most phenolic compounds are quickly
converted into their reaction products when the plant cells are in disarray. Therefore, it is difficult
FOOD POLYPHENOLS
Flavonoids
Flavones
Isoflavones
Flavonols
Proanthocyanidins
Flavanones
Phenolic Acids
Hydrocinnamic
Acids
Hydroxybenzioc
Acid
Lignin
Resveratrol
Stilbenes
Matairesinol
Secoisolariciresinol
Figure 15.3 Classification of food polyphenols.

15.2 Polyphenols: Classification, Health Benefits, Bioavailability 315
to incorporate food polyphenols into food compositions [19, 22]. Black tea has a well-established
history of producing certain tannin-like substances via enzymatic oxidation. It has been shown
that several chemical processes involving anthocyanins or flavanols occur during the aging of red
wine [17, 19, 21–25].
15.2.1.1 Phenolic Acids
Phenolics are classified as aromatic rings with OH groups connected as non-flavonoid polyphe-
nols. Benzoic acid, which has seven carbon atoms, and cinnamic acid, which has nine carbon
atoms, are the two main characteristics that set phenolic acids apart [17]. Because of their multiple
health benefits for humans, including their anti-inflammatory, anticancer, and antimicrobial qual-
ities, they are essential dietary components [23].
15.2.1.2 Flavonoids
Flavonoids are a component of the vibrant colors found in herbs, fruits, and vegetables [26]. They
can be further separated into flavonones, flavones, flavonols, flavan-3-ols, anthocyanidins, and
isoflavones depending on the variation in the C-ring [27]. Because of the pattern and intensity of
modifications of hydroxyl groups, methoxy groups, and glycan molecules, each of these subgroups
differs in certain ways. Flavonoids include substances such as quercetin, naringenin, catechin,
daidzein, and cyanidin-glucoside [28, 29]. They can exist in several modified forms in addition to
being free glycosidic conjugates and aglycones [30–32]. Additional categories of flavonoids include
flavones, flavonols, flavonones, isoflavones, and anthocyanins [33].
Flavanones are the most therapeutically important flavonoids that are present in all citrus fruits.
Hesperiden, narigenin, and eriodictyol are examples of a few flavonones. Anthocyanins are the
most significant subclass of flavonoids and naturally occurring pigments [34–36]. They are two
phenyl benzopyrylium salts that have had their polyhydroxy and polymethoxy derivatives glyco-
sylated. Black currants, red and merlot grapes, as well as raspberries, cranberries, strawberries,
blueberries, and bilberries all have them in the outermost layers. They could potentially replace
synthetic dyes and natural colors in the food companies [34–46].
15.2.1.3 Stilbenes
The non-flavonoid class of stilbenes comprises two phenyl rings bridged by a two-carbon methyl-
ene group. They are free isomers (cis and trans), with two aromatic rings, called A and B, in glyco-
sylated forms. Two hydroxyl groups are present at the m-position of ring A, whereas methoxy and
hydroxyl groups are substituted at several locations in ring B [47]. Stilbenes, such as resveratrol,
are often produced by berries, grapes, and nuts [48].
15.2.1.4 Lignans and Lignins
Another non-flavonoid molecule is lignan, which is made up of two C6–C3 units linked together
at positions 8 and 8′. Because the lignan C9 and C9′ positions are substituted in a variety of ways,
they have a wide range of structural forms categorized such as dibenzylbutane, furan, and arylte-
tralin [47]. Pulses, seeds, and vegetable oils are the principal sources of lignans because they lack
an abundance of glycosylated structures. Lignin is an aromatic biopolymer created when peroxi-
dase enzymes oxidize p-hydroxycinnamyl alcohol monomers in a phenolic reaction [49].
15.2.1.5 Tannins
Tannins are a class of high molecular weight, water-soluble phenolics. They can also be separated
into condensed tannins and hydrolyzable tannins. Galltannins and ellagitannins are two types of

15 Nanodelivery of Food Polyphenols for Nutraceutical Applications
316
hydrolyzable tannins. Phlorotannin, a kind of tannin that makes up 25% of the subcellular struc-
ture of brown algae, has recently attracted interest from the food, feed, and pharmaceutical indus-
tries [50]. As functional molecules with a variety of anti-activities towards cancer, microbes,
hypertensive, diabetic, and inflammatory effects, phlorotannins have shown a lot of promise [51].
These phenolic compounds could be exploited as antioxidants in the food industry because they
have excellent superoxide and free radical scavenging capabilities. They inhibit lipase in the pan-
creas that is responsible for the breakdown of dietary fats, and was eventually used as a weight loss
component [52].
15.2.2 Health Benefits
Polyphenols are secondary metabolites present in the kingdom Plantae. They provide significant
health advantages because of their immunomodulatory, antibacterial, anti-inflammatory, and
antioxidant capabilities [1, 2]. Polyphenols found in fruits, vegetables, tea, cocoa, and other foods
are good for human health. For instance, there is a significant link between cocoa flavan-3-ols and
a reduced risk of diabetes, myocardial infarction, and stroke. Additionally, dietary polyphenols
help reduce lipid profiles, bodily inflammation, insulin resistance, and blood pressure [4, 5].
Resveratrol, a stilbene, and the flavonoid quercetin have been connected to cardiovascular health.
It is possible that the capacity of dietary polyphenols has therapeutic effects that stem from a two-
way relationship with the gut microbiota. This is mostly because polyphenols are known to
improve human health by changing the composition of the gut microbiota [19]. Polyphenols are
transformed into bioactive molecules with therapeutic benefits by the gut flora. In this chapter, we
go through polyphenols’ antioxidant, anticytotoxicity, anti-inflammatory, antihypertensive, and
antidiabetic properties [21].
15.2.2.1 Antioxidant Activity
Polyphenols are functional and bioactive phytochemicals that have stirred interest from various
scientists, nutritionists, and consumers because of their health benefits. One such health benefit is
their antioxidant property. Typically, oxidative stress is induced by low levels of antioxidant
synthesis or high levels of reactive oxygen species (ROS), such as OH radicals and H2O2, during
various metabolic processes leading to chemical reactions triggering cell and tissue damage
[53–55]. Moreover, diseases like atherosclerosis, inflammation, cancer, diabetes, arthritis, and
even neurological disorders are caused by oxidative damage to cells [54–56]. Utilizing dietary plant
polyphenols and other naturally occurring antioxidants from plant-based foods can help the body
fight off oxidative stress and its harmful effects. Because of their essential role in disease preven-
tion, these phytochemicals rank among the most important natural antioxidants used by humans [57].
Because of their antioxidant properties and ability to scavenge ROS, phenolic compounds have the
potential to both treat and prevent several degenerative disorders [53]. According to research, eat-
ing foods high in polyphenols, such as fish and other seafood, which are natural antioxidants, can
help prevent lipid oxidation as well as morbidity brought on by degenerative diseases [58, 59].
Another important factor influencing the antioxidant capabilities of these bioactive substances is
the amount and position of the hydroxyl groups in phenols [60]. This group has a conjugation
impact leading to reduction in the hydrogen ion’s binding capacity [53]. Therefore, free radical
generation can be stopped by phenolic substances. The free radicals receive an electron transfer
through this mechanism, and after the radicals are neutralized, they become more stable. Thus,
the domino effect will be broken [17]. However, there is a direct correlation between the class of
plant species chosen and the kind of solvent used in the extraction processes and the potential

15.2 Polyphenols: Classification, Health Benefits, Bioavailability 317
antioxidant activity of phenolic compounds [61]. By using several mechanistic pathways, the poly-
phenols can exhibit antioxidant actions that reduce the generation of ROS [62]. According to
research, polyphenols can interact with ROS by giving unpaired electrons to free radicals or hydro-
gen atoms, which in turn produces stable phenolic oxygen radicals. Therefore, these bioactive
substances can remove the byproducts of free radicals [53]. Polyphenols, including tocopherols
and flavonoids, are typically regarded as important main antioxidant components. By using elec-
tron transfer processes, their aromatic amines can prevent autoxidation [63].
15.2.2.2 Antihypertensive Activity
Although hypertension is one of the major global causes of cardiovascular illnesses, its origins are
not well understood with no overt symptoms [63, 64]. To avoid the adverse effects of hypertension,
prevention and treatment have become essential. Dietary modifications are the main strategy for
controlling high blood pressure. The most effective non-pharmacological treatments include
reducing sodium intake, adding potassium supplements, increasing physical activity, and losing
weight [65]. Receptor blockers, angiotensin II receptor antagonists (ARBs), angiotensin-trans-
ferase inhibitors, calcium antagonists, and diuretics are only a few of the synthetic and chemical
drugs that the World Health Organization (WHO) prescribes for the treatment of hypertension
[66]. Although these medications have an efficient antihypertensive effect, they can also cause
vertigo, coughing, ankle edema, high blood cholesterol levels, and sodium and water retention.
Furthermore, these medications cannot be used for a long period to treat artery illness or reduce
the symptoms of hypertension [66, 67]. Endothelial dysfunction has reportedly been identified as
one of the symptoms of hypertension disease. Thus, the combination of endothelium-dependent
vasodilatation with oxidative damage serves as a defining characteristic of endothelial dysfunc-
tion. In actuality, this dysfunction is discovered prior to changes in the composition or texture of
the artery walls, and as a result, this dysfunctional state leads to the onset and development of
cardiovascular disorders [67, 68]. Several studies have confirmed that phenolic compounds and
their derivatives can enhance the performance of vascular endothelial cells through numerous
methods, including by inhibiting the production of pro-oxidant enzymes [68]. For example, the
COXs and NADPH oxidase may aid in enhancing endothelial function, slowing the aging of the
vascular system, and preventing hypertension [69]. Additionally, the phenolic compounds can
help lower the blood pressure by activating the mTORC2-Rictor survival pathway and suppressing
the production of mTOR signaling proteins [70]. Additionally, multiple research studies [71–74]
suggest that polyphenols may reduce the activation of the angiotensin system, and increase
endothelial relaxation by modifying EDH, oxidative stress, and inflammatory response in order to
enhance the angiotensin system and generate the vasodilation effect [69, 71, 73, 74]. Because of
their role in lowering systolic blood pressure in spontaneously hypertensive rats, polyphenols and
their derivatives have been shown to have a significant antihypertensive effect in other in vivo
research studies [75, 76]. Additionally, polyphenols effectively lower blood pressure through a
variety of methods of action. Polyphenol therapy for hypertension has been demonstrated to
improve endothelial function and relax vascular tissues by inhibiting ACE and related pathways
[64]. It has been shown that polyphenols can reduce the activity of metalloproteinases, especially
those that cause hypertension [64, 77].
15.2.2.3 Antimicrobial Activity
Microorganisms are to blame for several diseases and fatalities. However, overuse of synthetic
medications has increased the prevalence of resistant pathogenic forms of bacteria as well as

15 Nanodelivery of Food Polyphenols for Nutraceutical Applications
318
antimicrobial resistance. Consequently, the need for naturally occurring antibacterial chemicals
has increased [78–80]. Because of their numerous antimicrobial effects against a huge microbial
population, interest in polyphenols has increased. They also help address a wide spectrum of ben-
eficial microbes [79, 81].
The mode of action of polyphenols includes the disruption of the lipid membrane and altera-
tion of the structure causing a leak of the cellular components, disturbing intracellular func-
tions, and affecting the hydroxylation and oxidation levels [79, 80, 82]. The antimicrobial
activity is given in Figure 15.4. The antibacterial activity of polyphenols has been improved by
new extraction and encapsulation techniques [83–85]. Additionally, polyphenols have the
capacity to give antibacterial activity, changing the permeability of cells and destroying the
composition of cells as a result [63]. It is important to highlight that the hydroxyl group of phe-
nolic polyphenols contributes significantly to the death of bacterial cells. As a result, the den-
sity gradient across the plasma membrane is reduced when the OH of the polyphenolic
compound contacts the bacterial cell wall and it reduces the ATP pool, which causes microbial
cells to die [63]. In a case study, the antibacterial potential of phenolics from Japanese apricots
against Enterobacteria was examined [86]. The examined microorganisms were more resistant
to the antibacterial activity of phenols; however, only at comparatively greater doses (1,250–
5,000 g/mL). The outcomes of the chemical examination revealed the presence of chlorogenic
acid and hydroxycinnamic acid derivatives [87]. On vero E6 cells, the treatment dramatically
reduced the MTT assay at concentrations of 80 mg/mL and 100 g/mL. Similarly, the application
reduced the viral titer in the supernatant of infected treated cells and prevented virus reproduc-
tion for the 24 hours that were observed. Additionally, some studies have documented that
polyphenols have a unique capacity to shield humans against disease such as oral bacteria and
non-communicable viral diseases [88–93]. Polyphenols also have anticancer properties and
antiviral properties against COVID-19 [19].
Figure 15.4 Antimicrobial action of polyphenols.

15.3 Nanocarriers and Nanodelivery Methods 319
15.2.3 Bioavailability
Bioavailability refers to the extent to which a substance or a compound is made completely avail-
able to its intended biological destinations. Most polyphenolic compounds reveal low bioavailabil-
ity [9]. The reasons are usually linked to its sub-par bioaccessibility. Factors include its interaction
with the food matrix, metabolic processes, and food processing, which are mediated by the intes-
tine, liver, and microbiota, and can influence the bioavailability of polyphenolic compounds [94].
Polyphenols have powerful antioxidant, immunomodulatory, anticancer, prebiotic, and anti-
inflammatory properties; however, more research is needed to confirm their gastroprotective
activity. Natural polyphenols are anticarcinogenic and recommended for CRC chemoprevention
and treatment. Polyphenols may have pharmacological activity, particularly antitumor activity
[22]. Nanomedicine has the potential to improve tumor treatment by compensating for the low
bioavailability of polyphenols. Polyphenols have immunomodulatory consequences on mac-
rophages and may be utilitarian in the treatment and prevention of autoimmune diseases [95, 96].
The limited oral bioavailability of several polyphenolic substances limits their utility in nutraceu-
ticals. The silver lining is that green bio-based nanocarriers are ideal for encasing, protecting, and
dispersing polyphenols, hence enhancing bioavailability. When used as nutritional treatments,
bio-based polymers with higher biocompatibility, biodegradability, resource sustainability, and
nutrient content, such as proteins and polysaccharides, are appropriate delivery vehicles for
addressing the drawbacks of oral polyphenol utilization [13, 29]. Factors affecting bioavailability of
polyphenols are listed in Figure 15.5.
15.3 Nanocarriers and Nanodelivery Methods
15.3.1 Nanocarriers
15.3.1.1 Solid Lipid Nanoparticles
Various nanocarrier and nanodelivery systems are tabulated in Figure 15.7. Solid lipid nanoparti-
cles (SLNs) are colloidal nanocarriers of submicron size (50–1,000 nm) comprising lipids compat-
ible with human physiology. The SLNs are disseminated in an aqueous solution with surfactants.
Ultrasonication and microfluidization, often known as high-pressure homogenization, are two
Thermal treatment, homogenization, cooking and
methods of culinary preparation, storage
Food related factorsFood Matrix, Presence of positive or negative
factors for absorption
Interaction with other compounds Bonds with proteins or polyphenols with similar
mechanism of absorption
Polyphenols related factorsChemical structure, amount introduced and
concentration in diet
Host-related Factors Intestinal factors and systemic factors
External Factors Environmental factors and food availability
Food Processing related factors
Figure 15.5 Factors affecting bioavailability.

15 Nanodelivery of Food Polyphenols for Nutraceutical Applications
320
techniques used to create SLNs [97]. SLNs feature a large surface, a large pharmaceutical payload,
and improved interfacial contact because of their submicron size. Problems facing SLNs, which
include nanoemulsions, microemulsions, polymer NPs (refer to Figure 15.6), and liposomes, are
ineffective site-of-action targeting and uncontrolled release profiles [98]. A drug payload can be
delivered using one of two methods. The drug can be attached to the polymeric component’s sur-
face or embedded into the polymeric core. One of the primary benefits of SLNs is that they trap the
hydrophobic drug in a state of equilibrium without using hazardous chemical solvents. The size-
related features of SLNs, as well as their drug integration capabilities, are additional benefits [99].
It is easier to set up large-scale manufacturing, which has better bioavailability and fewer negative
effects. Differences in nucleic acid sizes and charge can impact lipid packing and the SLN struc-
ture. The molar proportion and fatty composition of the manufacturing techniques used to encap-
sulate nucleic acids in the systems must also be fine-tuned [98]. Additionally, surface-attached
ligands (such as folate and transferrin) can be included in the outer layer of the SLNs to tailor them
to recognize and bind to particular cell receptors.
Recently, two microfluidic mixing methods based on fast mixing have been developed. Staggered
herringbone mixing, a continuous flow method called microfluidic hydrodynamic focusing, is the
most widely applied method for producing lipid nanoparticles (LNPs) in a repeatable and scalable
manner [99]. By using this method, there is better control over the mixing process and it is quicker.
All of these approaches allow for the rapid mixing of a liquid layer, including nucleic acid and lipid
elements, producing large nucleic acid encapsulation [98]. Certain LNPs can be generated by pre-
cisely controlling microfluidic operational parameters.
Figure 15.6 Nanoparticles for polyphenol delivery.

15.3 Nanocarriers and Nanodelivery Methods 321
To generate a nanoemulsion, at least two immiscible liquids must be present, one of which is
water and another is a fat. The procedures used to manufacture these nanoformulations are
mechanical or chemical [97]. Hydrophobic chemicals and emulsifiers mix to generate nanoemul-
sion droplets, whereas, in a mechanical process, large emulsion droplets are homogenized under
tremendous pressure to form nanodroplets. The size and shape of the produced emulsion droplets
are significant characteristics that set nanoemulsion apart from a traditional emulsion; the size
ranges from 20 nm to 200 nm [97, 98, 100].
15.3.1.2 Nanocrystals
Nanocrystals are colloidal materials with a dimension of 20–850 nm that comprises drug mole-
cules distributed in various phases [101]. These nanocrystals, which can also be created chemically
or mechanically, benefit from fewer nanoscale particles and a large surface area to maintain
Figure 15.7 Common bio-based nanocarriers and nanodelivery systems.

15 Nanodelivery of Food Polyphenols for Nutraceutical Applications
322
contact with the dissolving phase. Two advantages of nanocrystals over conventional dosage forms
are enhanced saturation solubility and increased drug loading with faster dissolving rates [101].
15.3.1.3 Nanopolymerosomes (NPS)
Nanopolymerosomes (NPS) are aqueous-cored polymer forms that range in size from 10 nm to 1
mm because of amphiphilic copolymers. The programmable features of NPS, which may be used
to create synthetic organelles or drug delivery systems, allow for a wide range of biological bene-
fits. They are created in the same way as polymeric NPs [102]. Because of their customizable quali-
ties, several biodegradable and stimulation-responsive polymers are used in NPS to encapsulate
drugs and improve release behaviors. NPS are effective in incorporating both lipophilic and hydro-
philic pharmacological chemicals, namely a polymeric membrane bilayer and solvent core. NPS
have a broader variety of use than nanostructured lipid carriers (NLCs), a more persistent vesicu-
lar composition, and a regulated vesicular content [103, 104].
15.3.1.4 Liposomes
Liposomes are phospholipid bilayer sphere-like vesicles that have a watery core that are biode-
gradable. They develop when phospholipids self-assemble [62, 105]. Their structure allows hydro-
philic drug molecules to be loaded into the inner aqueous core and lipophilic medicinal compounds
to be loaded into the surrounding phospholipid bilayer. Liposomes can be created using several
techniques, including solvent injections, reversed-phase evaporation, and thin-film hydration.
Depending on their size and the quantity of phospholipid bilayers they contain, these vesicles are
categorized as unilamellar, multilamellar, or multivesicular [62, 105–107]. According to studies,
liposomal polyphenols have therapeutic effects. Curcumin liposomes have higher antioxidant
activity than uncomplexed curcumin. Researchers created a liposomal formulation of quercetin
and observed that it had improved solubility, bioavailability, and antitumor effectiveness in vivo
[108–111].
15.3.1.5 Ethosomes
These vesicular transporters are phospholipid-based and transport a sizable amount of ethanol.
Touitou and colleagues originally developed these vesicles to effectively transmit active drugs
through the epidermis [95]. The ethosome is a non-intrusive transport system. Because ethosomes
contain more ethanol, they charge the skin’s surface and make it easier to penetrate, better ena-
bling medicinal medications to permeate the skin’s underlying tissues for systemic circulation.
Mechanical dispersion, a cold method, hot method, and other procedures are used to create etho-
somes [112, 113]. A useful method to improve in situ stability, skin permeability for polyphenols,
bioavailability, and therapeutic efficacy has been proposed by adding phytopolyphenols to etho-
somes. Epigallocatechin-3-gallate (EGCG) was encapsulated in ethosomes, and researchers found
that EGCG increased the antioxidant activity and photostability. However, the ethosomal formula-
tion displayed greater in vivo skin targeting and efficacy against UVB radiation-induced skin
inflammation [95, 114, 115].
15.3.1.6 Phytosomes
Phytosomes are phospholipid and herbal medicinal extract combination vesicles. Phospholipids
can behave as active emulsifiers because of their polar head and lipid tail. The emulsifier charac-
teristic of phytosomes increases the bioavailability of phytopolyphenols by facilitating their transi-
tion from the aqueous to the lipophilic environment of the cell membrane [116]. When compared
with silybin alone, the composition of silybin phytosomes have better hepatoprotective and

15.3 Nanocarriers and Nanodelivery Methods 323
antioxidant capacities [117]. Ginkgo phytosomes have been linked to increased brain and vascular
protection. Furthermore, researchers created a transdermal product containing rutin phytosomes
and discovered that they had a significant effect on rheumatoid arthritis [118, 119].
15.3.1.7 Invasomes
Invasomes are phospholipid, ethanol, and terpene-based nanovesicular transdermal medication
delivery devices. Invasomes promote drug permeability within the epidermal layers by eroding the
stratum corneum’s lipid packing [120]. Invasomes have a greater therapeutic effect and enhanced
solubility as a medicinal carrier for phytopolyphenols. Scientists have created an invasive cream
made of Ocimum basilicum to cure acne, and they have seen how well the medicine works by pen-
etrating the epidermis [121].
15.3.1.8 Polymeric Nanocarriers
One of the most efficient and practical industrial methods for protecting and delivering phenolics
is the application of polymeric nanoforms and natural NP-based carriers. The preparation, use,
and characterization of polymeric-based nanocapsules and natural nanocarriers for phenolics
have been conducted [122]. These include polymeric NPs, polymeric complex NPs, cyclodextrins,
nanocaseins, nanocrystals, electrospun nanofibers, electrosprayed NPs, and nanosprayed dried
particles [122]. NPs are submicron solid fragments that can be employed to nanoencapsulate sub-
stances that are bioactive. NPs, nanospheres, or nanocapsules can be obtained depending on the
technique of preparation [123].
15.3.1.8.1 Nanocapsules
Systems that have a classic core–shell construction, where the medicine is contained within a liq-
uid cavity on the inside and encased by a polymeric sheet or cavity on the outside [122, 124].
15.3.1.8.2 Nanospheres
Drugs can either be adsorbed on the surface of the NPs or trapped in the continuous polymeric
network of solid matrix systems [83, 88].
15.3.1.8.3 Polymerosomes
Amphiphilic block copolymers self-assemble to create polymeric vesicles that have an aqueous
inside and a polymer shell [103].
15.3.1.8.4 Dendrimers
Dendritic polymers have central cores, branching repeat units, and terminal groups in 3D,
nanoscale, hyper-branched, well-defined, monodisperse topologies [56].
Nanodelivery systems are classified into two types: liquid and solid. The three types of fluid nan-
odelivery methods are nanoemulsions, nanoliposomes, and nanopolymersomes. Nanoemulsions
are either emulsions or stabilized emulsions. There are three varieties of solid nanodelivery meth-
ods: LNPs, polymeric NPs, and nanocrystals [125].
15.3.2 Nanodelivery Systems
NP delivery systems are designed technologies that employ NPs to deliver therapies in a targeted
and controlled manner. There are numerous effective drug delivery systems (Figure 15.8) that
have been employed in recent years; nevertheless, there are still obstacles that must be addressed,

15 Nanodelivery of Food Polyphenols for Nutraceutical Applications
324
and an improved technology must be created for successful drug delivery to its destinations. As a
result, research into nano-based drug delivery systems is being conducted to improve drug delivery
systems [125]. Richard Feynman first reported the idea of nanotechnology [126, 127].
There are two types of gene delivery strategies: viral and non-viral [128, 129]. There are potential
side effects of existing gene delivery systems, resulting in the scope for further research on new
gene delivery systems. Alternatively, non-viral gene delivery techniques have been developed
using bio-polymers [129, 130]. It is widely recognized that NPs offer unique advantages for bioac-
tive delivery, ranging from increased stability to regulated release, and targeting the bioactive for
more substantial functioning [131]. Biologically active plant substances are widely recognized for
their multiple medicinal properties; nevertheless, processing and storage instabilities restrict their
bioavailability and bioaccessibility [132, 133]. Microfluidization has recently emerged as a trans-
formative technique for creating methods of delivery with increased stability and accessibility of
encapsulated plant compounds that are bioactive such as solid lipid nanocarriers, nanoemulsions,
and liposomes.
The medical sector is intrigued by the possibility of nanodelivery systems created using micro-
fluidization methods to regulate delivery with improved health benefits for the curing of numer-
ous chronic illnesses. This study focuses on microfluidization-based nanodelivery technologies
and their applications in the treatment of chronic illnesses [132, 134, 135]. Recently, microfluidiza-
tion methods have been employed to develop nanodelivery systems with increased plant-based
bioactive chemical resistance and bioavailability. Microfluidization is a high energy technique that
operates on the dynamics of specifically engineered microchannels [132, 135]. Because of its
Figure 15.8 Process of extraction of polyphenols and their delivery systems. Credit: Danijela / Adobe Stock

15.3 Nanocarriers and Nanodelivery Methods 325
capacity-constrained permeation enhancement, microneedle-mediated NPs have a tremendous
potential and a wide range of applications [136, 137]. Nanodelivery/NP-based techniques have
been developed to target tumor cells or the tumor microenvironment, and non-coding RNA-based
medicines have the potential to be targeted therapies for cancer and other disorders [138–140].
Exosomes are a viable therapeutic nanodelivery platform because of their unique biological char-
acteristics, stability, and composition. Delivering smart silencers in a secure and effective manner
may be achieved by modifying synthetic NPs with exosome mimics [141–143]. The delivery sys-
tems are classified into four types:
1) Nanofabricated mode system
2) Carbohydrate mode system
3) Protein mode system
4) Lipid mode system
15.3.2.1 Nanofabricated Mode System
A common trend is the incorporation of functional food ingredients into food products to satisfy
customer requests for a healthy lifestyle. Because of their low dissolution in water, unpleasant
sensory nature, limited oral accessibility, and sensitivity to chemical degradation, these chemicals
are detrimental to the food matrix. For food applications, the nanoencapsulation technology wraps
bioactive substances in different nanofabricated delivery systems that are biocompatible and bio-
degradable [144–146].
15.3.2.2 Carbohydrate Mode System
Carbohydrate delivery systems feature outstanding characteristics such as biodegradability, abun-
dance, and the ability to adapt to functioning [147]. Cyclodextrin is a carbohydrate-based delivery
strategy that may be used to limit dietary bioactives that are less soluble, temperature sensitive, or
chemically fragile. Nanofabrication processes are used to develop carbohydrate-mode delivery
[147, 148].
15.3.2.3 Protein Mode System
Protein mode system techniques are popular because of their ability to incorporate both non-polar
and polar bioactive substances. They can be produced via spray drying and electro-hydrodynamic
techniques and they are mostly derived from plants, animals, and bacteria. Proteins from plants
have received attention recently in nanotechnology to protect and control hydrophobic bioactive
compounds, which has piqued the interest of the nutraceutical, food, and pharma sectors [149, 150].
Plant proteins are sustainable, eco-friendly, and energetic, which adds to their prospective func-
tion. To reduce the negative effects of employing raw material carriers, challenges must be over-
come to enhance their technological efficiency and boundaries. Although this plant protein
delivery method is limited and primarily used to transport lipophilic substances, further purifica-
tion or extraction technologies are needed to evaluate other properties. Moreover, protein physico-
chemical molecular principles govern protein mode nanocarriers. Antisolvent precipitation,
pH-driven gelation, and electrospray can all be used as preparation techniques [149–152].
15.3.2.4 Lipid Mode System
Lipid mode delivery systems, which were created for use in food applications, are the most effi-
cient encapsulation techniques because they can include materials with different solubilities,
enhance targeted delivery, and shield contents from free radicals [148, 153].

15 Nanodelivery of Food Polyphenols for Nutraceutical Applications
326
15.4 Polyphenol-based Nanodelivery
15.4.1 Nano-resveratrol
A polyphenolic compound called resveratrol is present in the skin of grapes and seeds, as well as
in trace quantities in peanuts, plums, and apples. It defends herbal plants from microbes and fungi
by functioning as a phytoalexin [121]. The redox properties of phenolic hydroxyl groups have a
substantial impact on resveratrol’s antioxidant ability. ROS can be eliminated by three of the OH
groups found in resveratrol. Additionally, resveratrol activates the endogenous antioxidant system
and the direct antioxidant pathway, which aids in cellular defense. The gene regulatory properties
of these polyphenolic compounds can be connected to their antioxidant properties [154, 155].
Down regulating the expression of NADPH oxidase inhibited the formation of ROS. When resvera-
trol enhanced mitochondrial biogenesis, the tetrahydrobiopterin-synthesizing enzyme GTP cyclo-
hydrolase-I was found to result in elevated antioxidant enzymatic levels and a decrease in
mitochondrial superoxide [155].
Recently, a few nanoscale delivery systems with resveratrol have drawn interest because of pos-
sible medicinal uses. In the visceral organs of male Wistar rats, one study discovered that resvera-
trol-loaded nanocapsules had a two times higher bioavailability than free drug. When resveratrol
is administered intravenously in its unprocessed state, the bioavailability of the medication was
increased by six times using folic acid bound serum albumin-encapsulated resveratrol polymeric
NPs [156, 157]. Resveratrol liposomes outperformed resveratrol alone in terms of solubility and
chemical stability. Because resveratrol is tightly bound to lipid molecules, which enhances nano-
resveratrol penetration as well as the sustained drug release effect, it has been observed that res-
veratrol SLNs could increase the penetration in keratocytes [99]. Additional research showed that
the formation of tumor cells was more effectively suppressed in a mouse model of xenograft ovar-
ian cancer when nano-resveratrol was combined with serum albumin. According to Shao et al.,
nano-resveratrol formulations based on methoxy-PEG-PCL showed more cytotoxic effects on
tumor cells than the free drug because of the improved cellular uptake [158, 159].
15.4.2 Nano-curcumin
Curcumin, a polyphenolic molecule with medicinal qualities, has been used as a spice and nutri-
tional supplement in Asian countries for a very long period. Rhizomes from the turmeric plant
(Curcuma longa) are used to make curcumin. Notably, it has three structural components, two of
which are phenolic groups and one of which is a diketone, all arranged in an aryl hydrocarbon
skeleton. Curcumin has neurological effects in addition to anti-inflammatory and anticancer prop-
erties [111]. Among the ailments it is used to treat are age-related disorders, inflammation, athero-
sclerosis, oxidative stress, cardiovascular disease, type-2 diabetes, rheumatoid arthritis, and ocular
problems.
Oral bioavailability of curcumin nanoformulations based on PLGA was 22 times greater
than that of the raw state. In a cerebral ischemia rat model, curcumin-loaded SLNs exhibited
a 16-fold increase in bioavailability [160]. Curcumin nanocapsules made with Eudragit RL100
polymer exhibit higher antioxidant capacity with reduced lipid peroxidation in dairy sheep milk.
Researchers discovered that curcumin invasomes have more anti-inflammatory and antioxi-
dant properties than other vesicular systems. Curcumin-loaded nanocomposites demonstrated
better anti- inflammatory activity [124]. Studies have shown that curcumin has the strongest
anti- inflammatory effect of any polyphenol when delivered in an altered dosage form using a

15.4 Polyphenol-based Nanodelivery 327
nanodelivery method [161]. The effectiveness of oral nano-curcumin formulation on individuals
with intermediate COVID-19 was evaluated in open, non-randomized clinical studies. In a 14-day
clinical trial, it was discovered that curcuminoids administered as nanomicelles significantly
speed up the healing process for symptoms like myalgia, fever, and tachypnea. Nano-curcumin
and omega-3 fatty acids cooperated to decrease the COX/iNOS mRNA gene in neuroinflammation,
possibly providing migraine sufferers with symptomatic relief [124].
15.4.3 Nano-genistein
The flavonoid genistein is a potent antioxidant. Two enzymes, sodium oxide dismutase and cata-
lase, are responsible for genistein’s antioxidant properties. Numerous severe diseases, such as
type-2 diabetes, osteoporosis, cancer, obesity, and neurodegeneration, have all been treated with it.
However, because of its poor bioavailability, it has significant clinical limits, and some side effects,
such as endocrine disruption and toxic consequences, have been recorded when used at larger
doses [162]. These limitations have been successfully overcome by nanotechnology, with poly-
meric nanomicelles containing genistein exhibiting better plasma profiles and bioavailability than
genistein alone [163]. When combined with lactoferrin, genistein NPs have also been demon-
strated to significantly lower poly-comb protein expression and postpone the development of oral
squamous cell carcinoma [164, 165].
15.4.4 EGCG-based Nanoforms
Green tea contains several important phytophenols, including (−)EGCG. Numerous pharmaco-
logical health benefits of EGCG have been reported, including functions as an antioxidant, tumor
chemoprevention, improved heart health, weight loss, and defense against ionizing fallout [166,
167]. Nanoformulations are being studied for their potential to improve the stomach environment,
systemic circulation transport capacity, and cancer targeting efficacy.
Nanoscale-based (lactide-co-glycolic acid) particles containing EGCGs were developed and stud-
ied for their anti-inflammatory capabilities because inflammation is a significant concern [166].
The anticancer and antiproliferative properties of EGCGs cause a marked arrest in the G1 phase of
the cell cycle and the production of apoptosis. The G1 phase is greatly prolonged by the chemopro-
tective and antiproliferative effects of EGCG on cancer [166–168].
15.4.5 Nano-kaempferol
Kaempferol is an anti-inflammatory agent found in a variety of plants and fruits. It is used to treat
a variety of conditions, including intervertebral disc degeneration, colitis, and fibroproliferative
disorders. To improve patient compliance and effectiveness, the bioavailability, solubility, adverse
drug reactions, and site-specific targeting must all be attained [115]. Poly(ethylene oxide)-
poly(propylene oxide)-poly(ethylene oxide) NPs significantly decreased cancer cell viability
because of their improved bioavailability compared with crude kaempferol [95]. When combined
with paclitaxel, kaempferol-containing NLCs showed increased activity against MDA-MB 468
breast cancer cells. In A549 lung cancer cells, kaempferol gold nanoclusters with improved mor-
phological properties and anticancer activity were investigated. Kaempferol NPs markedly
decreased the levels of cardiac enzymes, vascular endothelial growth factor expression, oxidative
stress, and increased heart tissue when compared with fluorouracil. These results were validated
by histopathology studies [169]. A kaempferol nanomatrix was layer-by-layer tuned to increase the

15 Nanodelivery of Food Polyphenols for Nutraceutical Applications
328
plasma and bone marrow content, boost the anabolic effect in osteopenic rats, and maximize bio-
availability. These nanocarriers may increase the bioavailability of medications, accumulate in
tumors, promote tumor cell uptake, combine therapeutic medicines with imaging methods, and
enhance anticancer properties. Clinical studies have demonstrated the anti-inflammatory, type-2
diabetes, and cardiotonic benefits of the dietary supplement nano-kaempferol, making it a promis-
ing treatment for a range of diseases [96].
15.4.6 Naringenin-based Nanoforms
Citrus fruits, such as bergamot, tomatoes, and cherries, contain a substance called naringenin
(NR). It has many pharmacokinetic properties, including antitumor, anti-inflammatory, and anti-
oxidant properties [53, 56]. However, NR’s therapeutic efficacy is limited by its strong hydropho-
bicity. NR can be added to nanodelivery vehicles, such as micelles, liposomes, SLN, nanosuspensions,
and others, to overcome this issue. Sustained-release NR NPs with greater oral bioavailability,
gastrointestinal tract absorption, and solubility were discovered to have increased anti-inflamma-
tory effects in the Freund’s adjuvant arthritis model [29, 41]. According to in vitro and in vivo
experiments, NR-based Eudragit E100 Cationic Polymeric Nanoparticles have increased absorp-
tion and bioavailability by approximately 96%, which increased the anticancer potential by approx.
16%. A mechanistic method that paired NR with a PLGA doxorubicin nanoparticulate system
demonstrated enhanced efficacy, a coactive effect, and decreased the toxicity. While an in vitro
breast cancer study revealed more potent selective antitumor action, an in vivo tumor cell toxicity
assay inhibited tumors in animal models [53, 56, 167]. Additionally, NR was effective in treating
Parkinson's disease. After rats were administered an intranasal dose of an NR-vitamin E-loaded
nanoemulsion, their behavioral activity returned to normal. The NR-loaded sulfobutylether–cyclo-
dextrin/chitosan NPs were demonstrated to be a useful alternative for ocular administration of
poorly soluble NR, with a sustained release and no irritating effects on the rabbit’s eye. When Nile
tilapia fish were exposed to NR NPs with an average size range of 165.1 nm, the oxidative stress
created by cadmium was reduced [170], potentially by the increased antioxidant capacity and
nano-NR bioaccumulation in liver and kidney cells. When NR is synthesized in the proper nano-
structure, it can be used to treat a variety of ailments, including cancer, neurological disorders,
liver diseases, ophthalmic disorders, inflammatory diseases, skin diseases, and diabetes. In a rand-
omized, placebo-controlled clinical experiment, nano-NR had hepatoprotective effects in obese
people, as well as secondary effects of decreased blood pressure and faster metabolism [170].
15.4.7 Apigenin-based Nanoform
Flavonoids are the most common type of polyphenol in plants, and apigenin (AG) is a highly
potent bioactive substance. Using both conventional and nanodelivery methods, researchers have
employed AG to treat conditions such as cancer, diabetes, Alzheimer’s disease, dementia, and
inflammatory illnesses [171]. The antidiabetic impact of AG-bilosomes was more effective than
that of a basic AG dispersion, and an optimized formulation of AG bilosomes provided better
release and penetration with a flux that was 4.49 times greater. A cancer cell with a high expression
of CD44 receptors was the target of an AG nanoassembly with a high drug loading and entrapment
efficacy [171, 172]. The formulation also offered an extended retention duration in the circulation
and sustained release.
PLGA-loaded AG NPs were created, and their efficiency in preventing UV-induced skin cancer
was assessed. By minimizing mitochondrial matrix edema brought on by greater carrier

15.4 Polyphenol-based Nanodelivery 329
penetration in tissues, nano-AG showed strong anticancer potential. In rat studies, they also
showed protective benefits against hepatocellular cancer [173]. Pharmacokinetics and biodistri-
bution investigations have shown a considerable increase in AG in systemic circulation, showing
the possibility for future patients with liver cancer. Nano-AG exhibits strong pharmacological
activity against a variety of cancer types. SLN with a high AG content (80.44% drug encapsula-
tion) and optimum particle size of approximately 161 nm was used to treat rheumatoid arthritis.
In AG-loaded mucoadhesive SLN, a chitosan covering increased absorption and the antioxidant
capacity [173]. Clinical experiments on nano-AG have revealed extraordinary effectiveness
against several malignancies. Nanotechnology could be used to improve apigenin’s solubility and
bioavailability profile, which has shown promising outcomes against the growth of breast cancer
cells [174].
15.4.8 Nano-theaflavins and Nano-thearubigins
The catechins in tea (Camellia sinensis) undergo enzymatic oxidation to produce theaflavins (TF)
and thearubigins (TR), two naturally occurring polyphenolic substances. The environmentally
friendly synthesis of nanoformulations uses these compounds [114, 115]. Tea leaves and green
synthesis nanotechnology principles were used to create gold NPs, which have enhanced antioxi-
dant and antibacterial properties. Silver NPs were also produced using green chemistry principles
with TF and TE to increase their antibiotic-induced bactericidal activity against Salmonella typhi
[16, 175].
To increase stability, absorption rate, intestinal epithelial cell targeting, and to stop TE and TF
from being oxidized, chitosan-based NPs can be nanoencapsulated. Black tea leaf extract was used
as a capping agent to stabilize the silver NPs made by electrolytic deposition using green nanotech-
nology [165]. A dose-dependent MTT experiment was conducted to examine their cancer resistant
effectiveness against HeLa cervical carcinoma cells. Another work used tea extract that has potent
antibacterial properties because of TE and TF to make stable gold and silver NPs. Polyelectrolyte-
encapsulated 200 nm gelatin-based NPs were created using the layer-by-layer method [165].
Hepatocyte growth factor-induced breast cancer cells are strongly inhibited by polyphenols cre-
ated from gelatinized NPs. Green nanotechnology was used to create gold NPs of tea polyphenols,
which had significant anti-prostate and anti-breast cancer cell line action. Clinical studies have
demonstrated the efficacy of TE and TF anti-inflammatory, antioxidant, anticancer, and anti-
osteoporotic medications. Blood cholesterol levels were considerably reduced by green tea
extracts [175, 176].
15.4.9 Quercetin Nanoforms
Quercetin (QT), a polyphenol with anti-inflammatory, anti-Alzheimer’s, anti-arthritic, wound-
healing, anti-ischemic, antihypertensive, antidiabetic, and antioxidant characteristics, has been
optimized for use in a range of pharmaceutical applications [53, 56]. A nanotechnology-based
formulation has shown considerable promise in the pharmaceutical area for improving numerous
physicochemical and biological properties of QT. In conjunction with doxorubicin, nano-QT was
used in the chemotherapeutic amelioration of apoptosis in cancer cell lines. An MTT assay was
used to look for antiproliferative effects, while RT-PCR was used to look for gene targeting poten-
tial [110, 176]. A nano-QT was synthesized and subjected to characterization tests before being
used in the quorum quenching of Streptococcus mutants using photodynamic therapy. This tech-
nique down regulated quorum-sensing system genes, eliminated microbial biofilm, and produced

15 Nanodelivery of Food Polyphenols for Nutraceutical Applications
330
the greatest ROS. By enhancing biopharmaceutical properties and improving the cell membrane
permeability, triphenylphosphonium-coated nano-QT was used to treat cerebral ischemia via ROS
[106, 110]. By regulating mitochondrial delivery and significantly increasing QT absorption in the
brain, oral treatment of nano-QT capsules lessened the severity of the histopathological changes.
Nano-QT was better than QT in avoiding matrix metalloproteinase-9 and oxidative stress-induced
gastric ulcers when it was examined for its capacity to halt mitochondrial damage in ethanol-
induced gastric ulcer rat models [176].
The development of biopharmaceuticals is benefited by the enhanced QT bioavailability and
carefully selected nanoformulation components of the nano-QT hydrogel. A clinical test using the
nano-QT hydrogel on the skin wounds of 56 diabetic patients considerably sped up wound healing
time as compared with a standard pharmacological treatment [177]. Intriguing pharmacological
effects of nano-QT on humans have also been discovered in other clinical research.
15.5 Current Advances
Current research on polyphenols has revealed their antibacterial and antifungal properties. It is
challenging to create a perfect, all-encompassing medicine because of their ubiquitous nature,
complicated structures, high virulence, and intricate processes of infections [161]. Furthermore,
these infections can avoid the negative effects of many treatments because of the development of
drug resistance and genetic changes. Contrary to traditional drug formulations, polyphenols work
through a variety of mechanisms by focusing on various cellular machinery and interfering with
these microorganisms’ main metabolic processes. Because of their variety of synergistic and immu-
nomodulatory processes, polyphenols rank among the best nutritional supplements with the
greatest ability to fight infections [178].
The systematic application of scientific knowledge to the operation and regulation of materials
on the nanoscale is known as nanotechnology. Food nanotechnology is a cutting-edge, fascinat-
ing, and rapidly expanding topic with numerous applications in the food sector. It is connected to
a wide range of fields [96]. Beneficial substances known as nutraceuticals are produced from
nutrients, herbal products, dietary supplements, and genetically modified “designed foods”. To
enhance the delivery mechanism of natural bioactive compounds and nutraceuticals, these are
nanofabricated. It not only increases efficacy and physicochemical stability, but also assures food
quality [169].
Food biotechnology can use nanofabrication as a tactic to increase the effectiveness of biomole-
cules. Organic antioxidants with polyphenolic structures, such as curcumin and resveratrol, can
prevent free radical damage, lessen lipid peroxidation, and inhibit DNA oxidation [179]. They may
work synergistically or additively when combined. Many nanofood delivery approaches have com-
bined curcumin and resveratrol to address their limited water solubility, bioavailability, and insta-
bility. There are significant challenges, including low entrapment efficiency, instability, a high rate
of leakage, and a lack of safety. To increase the stability of food NPs, a new food hyalurasome was
developed [51]. Hyaluronic acid (HA) is a polysaccharide polymer that occurs naturally and has
antioxidant properties both in vitro and in vivo. Oligo-HA (oHA) is a low molecular weight HA
with improved stability, bioavailability, and DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scav-
enging activity compared wtih normal HA. It also possesses a variety of functional features, includ-
ing immunostimulatory and antiangiogenic capabilities. Nutraceutical hyalurosome nano-food
delivery systems (CRHs) were developed using advanced nanotechnology to increase the stability,
bioavailability, and antioxidant activity of insoluble antioxidants [179, 180].

15.6 Challenges and Future Perspectives 331
Bioactive compounds, which are dietary metabolites that prevent cancer, are present in fruits
and vegetables. The stability and targeted delivery of biomolecules have improved with recent
efforts to encapsulate bioactive components in nanodelivery systems [117, 169]. For their potential
application in cancer therapy, a variety of nanodelivery techniques for bioactive substances,
including polymeric NPs, SLNs, NLCs, liposomes, niosomes, and nanoemulsions, have been stud-
ied. In vivo models and cancer cell lines were used in recent human clinical studies and effective-
ness analyses of the nanoformulations [131]. Because of the antiproliferative and pro-apoptotic
characteristics of tumor cells, nanodelivery techniques were developed to increase the therapeutic
effectiveness of bioactive compounds against a variety of cancers.
These substitutes were discovered and created to increase the effectiveness and security of new
herbal treatments [133]. It has been demonstrated that polyphenolics, flavonoids, bioactive pep-
tides, pigments, and essential fatty acids have medicinal or health benefits. Food science tech-
niques, such as nanoencapsulation and nanofabricated delivery systems, enhance food quality and
advance health [146]. Nanofabricated delivery methods based on lipids (solid and liquid), proteins,
and carbohydrates are a few examples. Toxicology assessments need to be further investigated to
guarantee the security of nanofabricated delivery systems, and advances in nanotechnology may
play a crucial role in the creation of functional foods [148].
15.6 Challenges and Future Perspectives
Combining multiple administration methods can enhance therapeutic effectiveness. Despite sig-
nificant improvements in human trials for gene delivery carriers, questions concerning how cer-
tain carriers are expected to target a particular nucleic acid to a particular specific cell type still
persist [70]. Although CVnCoV two-dose vaccinations showed only 47% efficiency in preventing
the disease, CureVac’s CVnCoV mRNA LNP vaccine for COVID-19 was a potential option [19]. It
employed a formulation similar to that of Pfizer and Moderna’s successful vaccines. These results
highlight the need to adapt the particle for the specific RNA sequence and the distinction between
modified vs. unmodified mRNA payloads used by Pfizer, Moderna, and CureVac [128, 181]. Next
generation gene delivery methods must consider material qualities, nucleic acid intracellular
activity and alterations, and disease characteristics.
Artificial intelligence algorithms and state-of-the-art robotic high screening technologies are
being developed to assess vast datasets of successful delivery vehicles. This primer focuses on sev-
eral aspects of DNA-based delivery that incorporate NPs, emphasizing the most crucial character-
istics that should be considered when developing delivery platforms and prospective production
methods [70]. It looks at the analysis of the findings, explains the methods for characterizing the
characteristics of nanomaterials, and helps infer possible biological impacts. The utilization of
nucleic acid NPs in bioanalysis, nano-barcoding, gene silencing and editing, vaccines, and immu-
notherapy are only a few of their numerous significant applications. Data reproducibility and dep-
osition are examined in relation to the field’s limits and optimization [131]. It is essential to
examine the toxicity of nano-coated materials and their various delivery mechanisms for bioactive
substances and nutraceuticals. Although the use of nanofabricated materials in food packaging is
expanding swiftly, there are still end-user regulatory and safety problems that need to be fully
explored and addressed. There is no worldwide legal regulation in force, and many nations still
lack governmental approval to assess the risk and safety of nanoencapsulated materials [128].
The full term for Steffen Foss Hansen’s “React Now” technique is Registration, Evaluation,
Authorization, Categorization, and Tools for Evaluating Nanomaterials Opportunities and

15 Nanodelivery of Food Polyphenols for Nutraceutical Applications
332
Weaknesses. To tackle food safety difficulties and successfully market nanofabricated program-
mable foods or nutraceuticals, organizations and businesses that work with nanofabricated mate-
rials must carefully analyze all of the aforementioned factors [181].
15.7 Conclusion
Secondary plant metabolites known as polyphenols have positive effects on human health and
food preservation. Because of the expanding interest in and variety of biological functions of these
products, the use of polyphenols as dietary supplements, antimicrobial medications, cosmetics,
and natural food preservatives is a trend that promises to be successful in the market [4, 182, 183].
Polyphenols are secondary metabolites that have potential health benefits for humans as dietary
sources of nutrition. When combined with nanotechnology-based drug delivery science, nutri-
tional supplements, herbal medicines, and spices have the potential to boost biological function
and overcome restrictions [154].
An encouraging development in the market is the use of polyphenols as alternatives to antibiot-
ics, prescription medications, and natural food preservatives. However, barriers to moving these
innovations to the industrial world persist [176]. The development of nanotechnology-based drug
delivery systems has several problems, including obtaining multifunctional systems, scale-up
methodologies, investigating targeting efficiency, meeting international criteria, and regulatory
concerns for toxicity profiles and biocompatibility [184]. The supply chain cannot support the
huge demand for polyphenols with the meager amount that is produced. As a result, extraction
methods have been devised that enable production via extraction even when it comes from
unconventional sources like organic waste. The development of novel methods, such as enzyme-
assisted extraction, supercritical fluid, and high-voltage electric discharge, is necessary. The
industrial uses are negatively impacted by the already low bioavailability of polyphenols as well
as their interactions with other compounds. As a result, nanocarriers were used to increase the
process efficiency [155].
NPs made from food macromolecules may improve the activity of polyphenols such as resvera-
trol, curcumin, and EGCG. They must endure the abrasive pH and environment created by diges-
tive enzymes in the GI tract, retain the loaded polyphenols throughout oral administration, and
then go to the small intestine, where the medicine is absorbed [83]. NP-based delivery systems can
improve the bioavailability and stability of pharmaceuticals and bioactive substances through a
variety of mechanisms. The method in which a substance interacts with the human body and its
profile of absorption, distribution, metabolism, and excretion will depend on its physicochemical
qualities, the behavior of the delivery system based on NPs, and morphological traits. The potential
dangers of NPs to human health are unknown. Comprehensive research should be performed in
this area [138].
References
1 Hano, C. and Tungmunnithum, D. (2020). Plant polyphenols, more than just simple natural
antioxidants: oxidative stress, aging and age-related diseases. MDPI. 26.
2 Quideau, S., Deffieux, D., Douat‐Casassus, C., and Pouységu, L. (2011). Plant polyphenols: chemical
properties, biological activities, and synthesis. Angewandte Chemie, International Edition in English
50 (3): 586–621.

References 333
3 Graf, B.A., Milbury, P.E., and Blumberg, J.B. (2005). Flavonols, flavones, flavanones, and human
health: epidemiological evidence. Journal of Medicinal Food 8 (3): 281–290.
4 Pandey, K.B. and Rizvi, S.I. (2009). Plant polyphenols as dietary antioxidants in human health
and disease. Oxidative Medicine and Cellular Longevity 2: 270–278.
5 Zhang, Z., Li, X., Sang, S. et al. (2022). Polyphenols as plant-based nutraceuticals: health effects,
encapsulation, nano-delivery, and application. Foods 11 (15): 2189.
6 Aziz, T., Ullah, A., Ali, A. et al. Manufactures of bio‐degradable and bio‐based polymers for
bio‐materials in the pharmaceutical field. Journal of Applied Polymer Science 139 (29): e52624.
7 Balla, E., Daniilidis, V., Karlioti, G. et al. Poly (lactic Acid): a versatile biobased polymer for the
future with multifunctional properties—From monomer synthesis, polymerization techniques
and molecular weight increase to PLA applications. Polymers 13 (11): 1822.
8 Ahmad, A., Gulraiz, Y., Ilyas, S., and Bashir, S. (2022). Polysaccharide based nano materials:
health implications. Food Hydrocolloids for Health 100075.
9 Subramanian, P. (2021). Lipid-based nanocarrier system for the effective delivery of
nutraceuticals. Molecules 26 (18): 5510.
10 Kalra, E.K. (2003). Nutraceutical-definition and introduction. American Association of
Pharmaceutical Scientists 5 (3): 27–28.
11 Das, L., Bhaumik, E., Raychaudhuri, U., and Chakraborty, R. (2012). Role of nutraceuticals in
human health. Journal of Food Science and Technology 49: 173–183.
12 Ajibola, A., Chamunorwa, J.P., and Erlwanger, K.H. (2012). Nutraceutical values of natural honey
and its contribution to human health and wealth. Nutrition & Metabolism 9 (1): 1–12.
13 Arshad, R., Gulshad, L., Haq, I.U. et al. (2021). Nanotechnology: a novel tool to enhance the
bioavailability of micronutrients. Food Science & Nutrition 9 (6): 3354–3361.
14 Fukushima, Y., Tashiro, T., Kumagai, A. et al. (2014). Coffee and beverages are the major
contributors to polyphenol consumption from food and beverages in Japanese middle-aged
women. Journal of Nutritional Science 3: e48.
15 Rahman, M.M., Rahaman, M.S., Islam, M.R. et al. (2021). Role of phenolic compounds in human
disease: current knowledge and future prospects. Molecules 27 (1): 233.
16 Grosso, G., Stepaniak, U., Topor-Mądry, R. et al. (2014). Estimated dietary intake and major
food sources of polyphenols in the polish arm of the HAPIEE study. Nutrition 30 (11–12):
1398–1403.
17 Tsao, R. (2010). Chemistry and biochemistry of dietary polyphenols. Nutrients 2 (12): 1231–1246.
18 Cheynier, V. (2005). Polyphenols in foods are more complex than often thought. The American
Journal of Clinical Nutrition 81 (1): 223S–229S.
19 Rathod, N.B., Elabed, N., Punia, S. et al. (2023). Recent developments in polyphenol applications
on human health: a review with current knowledge. Plants 12 (6): 1217.
20 Tsimogiannis, D. and Oreopoulou, V. (2019). Classification of phenolic compounds in plants. In:
Polyphenols in plants, 263–284. Academic Press.
21 Vuolo, M., Lima, V., and Maróstica, M. (2019). Chapter 2-Phenolic Compounds: Structure,
Classification, and Antioxidant Power, Editor (S): Maira Rubi Segura Campos. 33–50. Bioactive
Compounds, Woodhead Publishing.
22 Abbas, M., Saeed, F., Anjum, F.M. et al. (2017). Natural polyphenols: an overview. International
Journal of Food Properties 20 (8): 1689–1699.
23 Kumar, N. and Goel, N. (2019). Phenolic acids: natural versatile molecules with promising
therapeutic applications. Biotechnology Reports 24: e00370.
24 Ziegler, V., Ferreira, C.D., Hoffmann, J.F. et al. (2018). Cooking quality properties and free and
bound phenolics content of brown, black, and red rice grains stored at different temperatures for
six months. Food Chemistry 242: 427–434.

15 Nanodelivery of Food Polyphenols for Nutraceutical Applications
334
25 Dias, R., Pereira, C.B., Pérez-Gregorio, R. et al. (2021). Recent advances on dietary polyphenol’s
potential roles in celiac disease. Trends in Food Science & Technology 107: 213–225.
26 Kanwal, Q., Hussain, I., Siddiqui, L.H., and Javaid, A. (2011). Antimicrobial activity screening of
isolated flavonoids from Azadirachta indica leaves. Journal of the Serbian Chemical Society 76 (3):
375–384.
27 Wang, T.-Y., Li, Q., and Bi, K.-S. (2018). Bioactive flavonoids in medicinal plants: structure, activity
and biological fate. Asian Journal of Pharmaceutical Sciences 13 (1): 12–23.
28 Dai, J. and Mumper, R.J. (2010). Plant phenolics: extraction, analysis and their antioxidant and
anticancer properties. Molecules 15 (10): 7313–7352.
29 Kanwal, Q., Hussain, I., Siddiqui, L.H., and Javaid, A. (2011). Polyphenols, dietary sources and
bioavailability. Annali-IstitutoSuperiore di Sanita 43 (4): 348.
30 Cuyckens, F. and Claeys, M. (2004). Mass spectrometry in the structural analysis of flavonoids.
Journal of Mass Spectrometry 39 (1): 1–15.
31 He, X.-G. (2000). On-line identification of phytochemical constituents in botanical extracts by
combined high-performance liquid chromatographic–diode array detection–mass spectrometric
techniques. Journal of Chromatography A 880 (1–2): 203–232.
32 Stobiecki, M., Malosse, C., Kerhoas, L. et al. (1999). Detection of isoflavonoids and their glycosides
by liquid chromatography/electrospray ionization mass spectrometry in root extracts of lupin
(Lupinus albus). phytochemical analysis. An International Journal of Plant Chemical and
Biochemical Techniques 10 (4): 198–207.
33 Jiang, N., Doseff, A.I., and Grotewold, E. (2016). Flavones: from biosynthesis to health benefits.
Plants 5 (2): 27.
34 Pojer, E., Mattivi, F., Johnson, D., and Stockley, C.S. (2013). The case for anthocyanin
consumption to promote human health: a review. Comprehensive Reviews in Food Science and
Food Safety 12 (5): 483–508.
35 de Gaulejac, N.S.-C., Glories, Y., and Vivas, N. (1999). Free radical scavenging effect of
anthocyanins in red wines. Food Research International 32 (5): 327–333.
36 Corradini, E., Foglia, P., Giansanti, P. et al. (2011). Flavonoids: chemical properties and analytical
methodologies of identification and quantitation in foods and plants. Natural Product Research 25
(5): 469–495.
37 Lao, F. and Giusti, M.M. (2018). Extraction of purple corn (Zea mays L.) cob pigments and
phenolic compounds using food-friendly solvents. Journal of Cereal Science 80: 87–93.
38 Khoo, H.E., Azlan, A., Tang, S.T., and Lim, S.M. (2017). Anthocyanidins and anthocyanins:
colored pigments as food, pharmaceutical ingredients, and the potential health benefits. Food &
Nutrition Research 61 (1): 1361779.
39 Khan, M.K. and Dangles, O. (2014). A comprehensive review on flavanones, the major citrus
polyphenols. Journal of Food Composition and Analysis 33 (1): 85–104.
40 Panche, A.N., Diwan, A.D., and Chandra, S.R. (2016). Flavonoids: an overview. Journal of
Nutritional Science 5: e47.
41 Hsiao, Y.-H., Ho, C.-T., and Pan, M.-H. (2020). Bioavailability and health benefits of major
isoflavone aglycones and their metabolites. Journal of Functional Foods 74: 104164.
42 Alara, O.R., Abdurahman, N.H., and Ukaegbu, C.I. (2021). Extraction of phenolic compounds: a
review. Current Research in Food Science 4: 200–214.
43 Bolca, S. (2014). Bioavailability of soy-derived isoflavones and human breast cancer. In:
Polyphenols in human health and disease, 1241–1256. Academic Press.
44 Malla, A. and Ramalingam, S. (2018). Health perspectives of an isoflavonoid genistein and its
quantification in economically important plants. In: Role of Materials Science in Food
Bioengineering, 353–379. Academic Press.

References 335
45 Robards, K., Li, X., Antolovich, M., and Boyd, S. (1997). Characterisation of citrus by
chromatographic analysis of flavonoids. Journal of the Science of Food and Agriculture 75 (1):
87–101.
46 Hollman, P.C.H. and Arts, I.C.W. (2000). Flavonols, flavones and flavanols–nature, occurrence
and dietary burden. Journal of the Science of Food and Agriculture 80 (7): 1081–1093.
47 Singla, R.K., Dubey, A.K., Garg, A. et al. (2019). Natural Polyphenols: Chemical Classification,
Definition of Classes, Subcategories, and Structures. 1397–1400. Oxford University Press.
48 Han, X., Shen, T., and Lou, H. (2007). Dietary polyphenols and their biological significance.
International Journal of Molecular Sciences 8 (9): 950–988.
49 Pereira, D.M., Valentão, P., Pereira, J.A., and Andrade, P.B. (2009). Phenolics: From chemistry to
biology. Molecular Diversity Preservation International. 2202–2211.
50 Koeberle, A. and Werz, O. (2014). Multi-target approach for natural products in inflammation.
Drug Discovery Today 19 (12): 1871–1882.
51 Charoensiddhi, S., Abraham, R.E., Su, P., and Zhang, W. (2020). Seaweed and seaweed-derived
metabolites as prebiotics. Advances in Food and Nutrition Research 91: 97–156.
52 Qin, Y. (2018). Applications of Bioactive Seaweed Substances in Functional Food Products, in
Bioactive Seaweeds for Food Applications. 111–134. Elsevier.
53 Yan, Z., Zhong, Y., Duan, Y. et al. (2020). Antioxidant mechanism of tea polyphenols and its
impact on health benefits. Animal Nutrition 6 (2): 115–123.
54 Inanli, A.G., Tümerkan, E.T.A., El Abed, N. et al. (2020). The impact of chitosan on seafood
quality and human health: a review. Trends in Food Science & Technology 97: 404–416.
55 Kumarappan, C., Thilagam, E., and Mandal, S.C. (2012). Antioxidant activity of polyphenolic
extracts of Ichnocarpus frutescens. Saudi Journal of Biological Sciences 19 (3): 349–355.
56 Lee, C.Y., Nanah, C.N., Held, R.A. et al. (2015). Effect of electron donating groups on polyphenol-
based antioxidant dendrimers. Biochimie 111: 125–134.
57 Mihanfar, A., Nouri, M., Roshangar, L., and Khadem-Ansari, M.H. (2021). Polyphenols: natural
compounds with promising potential in treating polycystic ovary syndrome. Reproductive Biology
21 (2): 100500.
58 Rathod, N.B., Ranveer, R.C., Benjakul, S. et al. (2021). Recent developments of natural
antimicrobials and antioxidants on fish and fishery food products. Comprehensive Reviews in Food
Science and Food Safety 20 (4): 4182–4210.
59 Saeed, N., Khan, M.R., and Shabbir, M. (2012). Antioxidant activity, total phenolic and total
flavonoid contents of whole plant extracts Torilisleptophylla L. BMC Complementary and
Alternative Medicine 12: 1–12.
60 Li, Q., Li, J., Duan, M. et al. (2022). Impact of food additive titanium dioxide on the polyphenol
content and antioxidant activity of the apple juice. LWT 154: 112574.
61 Martins, N., Barros, L., and Ferreira, I.C. (2016). In vivo antioxidant activity of phenolic
compounds: facts and gaps. Trends in Food Science & Technology 48: 1–12.
62 Emami, S., Azadmard-Damirchi, S., Peighambardoust, S.H. et al. (2016). Liposomes as carrier
vehicles for functional compounds in food sector. Journal of Experimental Nanoscience 11 (9):
737–759.
63 Bensid, A., El Abed, N., Houicher, A. et al. (2022). Antioxidant and antimicrobial preservatives:
properties, mechanism of action and applications in food–a review. Critical Reviews in Food
Science and Nutrition 62 (11): 2985–3001.
64 Hügel, H.M., Jackson, N., May, B. et al. (2016). Polyphenol protection and treatment of
hypertension. Phytomedicine 23 (2): 220–231.

15 Nanodelivery of Food Polyphenols for Nutraceutical Applications
336
65 Micucci, M., Bolchi, C., Budriesi, R. et al. (2020). Antihypertensive phytocomplexes of proven
efficacy and well-established use: mode of action and individual characterization of the active
constituents. Phytochemistry 170: 112222.
66 Cao, Y., Xie, L., Liu, K. et al. (2021). The antihypertensive potential of flavonoids from Chinese
herbal medicine: a review. Pharmacological Research 174: 105919.
67 Lamb, S.A., Al Hamarneh, Y.N., Houle, S.K. et al. (2018). Hypertension Canada’s 2017 guidelines
for diagnosis, risk assessment, prevention and treatment of hypertension in adults for
pharmacists: an update. Canadian Pharmacists Journal/Revue Des Pharmaciens du Canada 151
(1): 33–42.
68 Yamagata, K., Tagami, M., and Yamori, Y. (2015). Dietary polyphenols regulate endothelial
function and prevent cardiovascular disease. Nutrition 31 (1): 28–37.
69 Oak, M.H., Auger, C., Belcastro, E. et al. (2018). Potential mechanisms underlying cardiovascular
protection by polyphenols: role of the endothelium. Free Radical Biology and Medicine 122:
161–170.
70 Sanches-Silva, A., Testai, L., Nabavi, S.F. et al. (2020). Therapeutic potential of polyphenols in
cardiovascular diseases: regulation of mTOR signaling pathway. Pharmacological Research 152:
104626.
71 An, P., Wan, S., Luo, Y. et al. (2022). Micronutrient supplementation to reduce cardiovascular risk.
Journal of the American College of Cardiology 80 (24): 2269–2285.
72 Delgado, N.T., Rouver, W.N., and Dos Santos, R.L. (2020). Protective effects of pomegranate in
endothelial dysfunction. Current Pharmaceutical Design 26 (30): 3684–3699.
73 Tropea, T., Renshall, L.J., Nihlen, C. et al. (2020). Beetroot juice lowers blood pressure and
improves endothelial function in pregnant eNOS−/− mice: importance of nitrate‐independent
effects. The Journal of Physiology 598 (18): 4079–4092.
74 Valero, M.S., Nuñez, S., and Les, F. et al. (2022). The potential role of everlasting flower
(Helichrysum stoechasMoench) as an antihypertensive agent: vasorelaxant effects in the rat aorta.
Antioxidants 11 (6): 1092.
75 Chan, S.-L., Capdeville-Atkinson, C., and Atkinson, J. (2008). Red wine polyphenols improve
endothelium-dependent dilation in rat cerebral arterioles. Journal of Cardiovascular
Pharmacology 51 (6): 553–558.
76 López-Sepúlveda, R., Jiménez, R., Romero, M. et al. (2008). Wine polyphenols improve endothelial
function in large vessels of female spontaneously hypertensive rats. Hypertension 51 (4):
1088–1095.
77 Botden, I.P., Langendonk, J.G., Meima, M.E. (2011). Daily red wine consumption improves
vascular function by a soluble guanylyl cyclase-dependent pathway. American Journal of
Hypertension 24 (2): 162–168.
78 Hyldgaard, M. (2020). Mechanisms of action, resistance, and stress adaptation. In: Antimicrobials
in Food 735–784. CRC Press.
79 Othman, L., Sleiman, A., and Abdel-Massih, R.M. (2019). Antimicrobial activity of polyphenols
and alkaloids in middle eastern plants. Frontiers in Microbiology 10: 911.
80 Zamuz, S., Munekata, P.E., Dzuvor, C.K. et al. (2021). The role of phenolic compounds against
Listeria monocytogenes in food. A review. Trends in Food Science & Technology 110: 385–392.
81 López-Malo, A., Alzamora, S.M., Paris, M.J. et al. (2020). Naturally occurring compounds–Plant
sources. Antimicrobials in food 527–594.
82 Freitas, I.R. and Cattelan, M.G. (2018). Antimicrobial and antioxidant properties of essential oils
in food systems—An overview. Microbial contamination and food degradation 443–470.

References 337
83 Saini, A., Panwar, D., Panesar, P.S., and Bera, M.B. (2021). Encapsulation of functional
ingredients in lipidic nanocarriers and antimicrobial applications: a review. Environmental
Chemistry Letters 19: 1107–1134.
84 Ferrentino, G., Haman, N., Morozova, K. et al. (2021). Phenolic compounds extracted from spruce
(Picea abies) by supercritical carbon dioxide as antimicrobial agents against gram-positive
bacteria assessed by isothermal calorimetry. Journal of Thermal Analysis and Calorimetry 145:
3093–3103.
85 Dzah, C.S., Duan, Y., Zhang, H. et al. (2020). The effects of ultrasound assisted extraction on
yield, antioxidant, anticancer and antimicrobial activity of polyphenol extracts: a review. Food
Bioscience 35: 100547.
86 Mitani, T., Ota, K., Inaba, N. et al. (2018). Antimicrobial activity of the phenolic compounds of
Prunus mume against Enterobacteria. Biological and Pharmaceutical Bulletin 41 (2): 208–212.
87 De Angelis, M., Della-Morte, D., Buttinelli, G. et al. (2021). Protective role of combined
polyphenols and micronutrients against influenza A virus and SARS-CoV-2 infection in vitro.
Biomedicines 9 (11): 1721.
88 Koch, W. (2019). Dietary polyphenols—important non-nutrients in the prevention of chronic
noncommunicable diseases. A Systematic Review. Nutrients 11 (5): 1039.
89 Abenavoli, L., Larussa, T., Corea, A. et al. (2021). Dietary polyphenols and non-alcoholic fatty
liver disease. Nutrients 13 (2): 494.
90 Margină, D., Ungurianu, A., Purdel, C. et al. (2020). Analysis of the intricate effects of
polyunsaturated fatty acids and polyphenols on inflammatory pathways in health and disease.
Food and Chemical Toxicology 143: 111558.
91 Rudrapal, M., Khairnar, S.J., Khan, J. et al. (2022). Dietary polyphenols and their role in oxidative
stress-induced human diseases: Insights into protective effects, antioxidant potentials and
mechanism (s) of action. Frontiers in Pharmacology 13: 283.
92 Li, Y., Jiang, X., Hao, J. et al. (2019). Tea polyphenols: application in the control of oral
microorganism infectious diseases. Archives of Oral Biology 102: 74–82.
93 Montenegro-Landívar, M.F., Tapia-Quirós, P., Vecino, X. et al. (2021). Polyphenols and their
potential role to fight viral diseases: an overview. Science of the Total Environment 801: 149719.
94 D’Archivio, M., Filesi, C., Varì, R. et al. (2010). Bioavailability of the polyphenols: status and
controversies. International Journal of Molecular Sciences 11 (4): 1321–1342.
95 Faisal, W., Soliman, G.M., and Hamdan, A.M. (2018). Enhanced skin deposition and delivery of
voriconazole using ethosomal preparations. Journal of Liposome Research 28 (1): 14–21.
96 D’Archivio, M., Filesi, C., Varì, R. et al. (2010). Bioavailability of the polyphenols: status and
controversies. International Journal of Molecular Sciences 11 (4): 1321–1342.
97 Carlotti, M.E., Sapino, S., Ugazio, E. et al. (2012). Resveratrol in solid lipid nanoparticles. Journal
of Dispersion Science and Technology 33 (4): 465–471.
98 Desai, J. and Thakkar, H. (2016). Effect of particle size on oral bioavailability of darunavir-loaded
solid lipid nanoparticles. Journal of Microencapsulation 33 (7): 669–678.
99 Teskač, K. and Kristl, J. (2010). The evidence for solid lipid nanoparticles mediated cell uptake of
resveratrol. International Journal of Pharmaceutics 390 (1): 61–69.
100 Ishkeh, S.R., Shirzad, H., Asghari, M. et al. (2021). Effect of chitosan nanoemulsion on enhancing
the phytochemical contents, health-promoting components, and shelf life of raspberry (Rubus
sanctus Schreber). Applied Sciences 11 (5): 2224.
101 Zhang, J., Huang, Y., Liu, D. et al. (2013). Preparation of apigenin nanocrystals using supercritical
antisolvent process for dissolution and bioavailability enhancement. European Journal of
Pharmaceutical Sciences 48 (4–5): 740–747.

15 Nanodelivery of Food Polyphenols for Nutraceutical Applications
338
102 Hashemi, M., Shamshiri, A., Saeedi, M. et al. (2020). Aptamer-conjugated PLGA nanoparticles for
delivery and imaging of cancer therapeutic drugs. Archives of Biochemistry and Biophysics 691:
108485.
103 Rudrapal, M., Vallinayagam, S., Zothantluanga, J.H. et al. (2022). Nanophytomedicines: nature to
medicines. In: Applications of Nanotechnology in Drug Discovery and Delivery, 71–93. Elsevier.
104 Khan, J., Rudrapal, M., Bhat, E.A. et al. (2021). Perspective insights to bio-nanomaterials for the
treatment of neurological disorders. Frontiers in Bioengineering and Biotechnology 9: 724158.
105 Karn, P.R., Cho, W., and Hwang, S.-J. (2013). Liposomal drug products and recent advances in the
synthesis of supercritical fluid-mediated liposomes. Nanomedicine 8 (9): 1529–1548.
106 Huang, Y.B., Tsai, M.J., Wu, P.C. et al. (2011). Elastic liposomes as carriers for oral delivery and
the brain distribution of (+)-catechin. Journal of Drug Targeting 19 (8): 709–718.
107 Guimarães, D., Cavaco-Paulo, A., and Nogueira, E. (2021). Design of liposomes as drug delivery
system for therapeutic applications. International Journal of Pharmaceutics 601: 120571.
108 El-Samaligy, M.S., Afifi, N.N., and Mahmoud, E.A. (2006). Evaluation of hybrid liposomes-
encapsulated silymarin regarding physical stability and in vivo performance. International
Journal of Pharmaceutics 319 (1–2): 121–129.
109 Coimbra, M., Isacchi, B., van Bloois, L. et al. (2011). Improving solubility and chemical stability of
natural compounds for medicinal use by incorporation into liposomes. International Journal of
Pharmaceutics 416 (2): 433–442.
110 Yuan, Z.P., Chen, L.J., Fan, L.Y. et al. (2006). Liposomal quercetin efficiently suppresses growth of
solid tumors in murine models. Clinical Cancer Research 12 (10): 3193–3199.
111 Tønnesen, H.H., Smistad, G., Ågren, T., and Karlsen, J. (1993). Studies on curcumin and
curcuminoids. XXIII: effects of curcumin on liposomal lipid peroxidation. International Journal
of Pharmaceutics 90 (3): 221–228.
112 Paliwal, S., Tilak, A., Sharma, J. et al. (2019). Flurbiprofen loaded ethosomes-transdermal
delivery of anti-inflammatory effect in rat model. Lipids in Health and Disease 18 (1): 1–15.
113 Verma, P. and Pathak, K. (2010). Therapeutic and cosmeceutical potential of ethosomes: an
overview. Journal of Advanced Pharmaceutical Technology & Research 1 (3): 274.
114 Godin, B., Touitou, E., Rubinstein, E. et al. (2005). A new approach for treatment of deep skin
infections by an ethosomal antibiotic preparation: an in vivo study. Journal of Antimicrobial
chemotherapy 55 (6): 989–994.
115 El-Kayal, M., Nasr, M., Elkheshen, S., and Mortada, N. (2019). Colloidal (-)-epigallocatechin-3-
gallate vesicular systems for prevention and treatment of skin cancer: a comprehensive
experimental study with preclinical investigation. European Journal of Pharmaceutical Sciences
137: 104972.
116 Saneja, A., Panda, A.K., and Lichtfouse, E. (eds.) (2020). Sustainable Agriculture Reviews 43:
Pharmaceutical Technology for Natural Products Delivery Vol. 1 Fundamentals and Applications
(Vol. 43). Springer Nature.
117 Bijak, M. (2017). Silybin, a major bioactive component of milk thistle (Silybum marianum L.
Gaernt.)—Chemistry, bioavailability, and metabolism. Molecules 22 (11): 1942.
118 Das, M.K. and Kalita, B. (2014). Design and evaluation of phyto-phospholipid complexes
(phytosomes) of rutin for transdermal application. Journal of Applied Pharmaceutical Science 4
(10): 051–057.
119 Amin, T. and Bhat, S.V. (2012). A review on phytosome technology as a novel approach to
improve the bioavailability of nutraceuticals. International Journal of Advanced Research in
Engineering and Technology 1 (3): 43–57.

References 339
120 Nangare, S. and Dugam, S. (2020). Smart invasome synthesis, characterizations, pharmaceutical
applications, and pharmacokinetic perspective: a review. Future Journal of Pharmaceutical
Sciences 6 (1): 1–21.
121 Celik, I., Rudrapal, M., Yadalam, P.K. et al. (2022). Resveratrol and its natural analogues inhibit
RNA dependant RNA polymerase (RdRp) of Rhizopus oryzae in mucormycosis through
computational investigations. Polycyclic Aromatic Compounds 1–18.
122 Nagaich, U. (2018). Polymeric nanocapsules: an emerging drug delivery system. Journal of
Advanced Pharmaceutical Technology & Research 9 (3): 65.
123 Sekhon, B.S. (2010). Food nanotechnology–an overview. Nanotechnology, Science and
Applications 1–15.
124 Zanotto-Filho, A., Coradini, K., Braganhol, E. (2013). Curcumin-loaded lipid-core nanocapsules
as a strategy to improve pharmacological efficacy of curcumin in glioma treatment. European
Journal of Pharmaceutics and Biopharmaceutics 83 (2): 156–167.
125 Patra, J.K., Das, G., Fraceto, L.F. et al. (2018). Nano based drug delivery systems: recent
developments and future prospects. Journal of Nanobiotechnology 16 (1): 1–33.
126 Lawal, S.K., Olojede, S.O., Faborode, O.S. et al. (2022). Nanodelivery of antiretroviral drugs to
nervous tissues. Frontiers in Pharmacology 13: 1025160.
127 Bayda, S., Adeel, M., Tuccinardi, T. et al. (2019). The history of nanoscience and nanotechnology:
from chemical–physical applications to nanomedicine. Molecules 25 (1): 112.
128 Mendes, B.B., Conniot, J., Avital, A. et al. (2022). Nanodelivery of nucleic acids. Nature Reviews
Methods Primers 2 (1): 24.
129 Nayerossadat, N., Maedeh, T., and Ali, P.A. (2012). Viral and nonviral delivery systems for gene
delivery. Advanced Biomedical Research 1.
130 Ramamoorth, M. and Narvekar, A. (2015). Non viral vectors in gene therapy-an overview. Journal
of Clinical and Diagnostic Research: JCDR 9 (1): GE01.
131 Borel, T. and Sabliov, C. (2014). Nanodelivery of bioactive components for food applications:
types of delivery systems, properties, and their effect on ADME profiles and toxicity of
nanoparticles. Annual Review of Food Science and Technology 5: 197–213.
132 Ganesan, P., Karthivashan, G., Park, S.Y. et al. (2018). Microfluidization trends in the
development of nanodelivery systems and applications in chronic disease treatments.
International Journal of Nanomedicine 6109–6121.
133 Rein, M.J., Renouf, M., Cruz‐Hernandez, C. et al. (2013). Bioavailability of bioactive food
compounds: A challenging journey to bioefficacy. British Journal of Clinical Pharmacology 75 (3):
588–602.
134 Pingale, P., Kendre, P., Pardeshi, K., and Rajput, A. (2023). An emerging era in manufacturing of
drug delivery systems: nanofabrication techniques. Heliyon 9 (3).
135 Ozturk, O.K. and Turasan, H. (2021). Applications of microfluidization in emulsion-based
systems, nanoparticle formation, and beverages. Trends in Food Science & Technology 116:
609–625.
136 Jiang, X., Zhao, H., and Li, W. (2022). Microneedle-mediated transdermal delivery of drug-
carrying nanoparticles. Frontiers in Bioengineering and Biotechnology 10: 121.
137 Ruan, S., Zhang, Y., and Feng, N. (2021). Microneedle-mediated transdermal nanodelivery
systems: a review. Biomaterials Science 9 (24): 8065–8089.
138 Sabit, H., Abdel-Hakeem, M., Shoala, T. et al. (2022). Nanocarriers: a reliable tool for the delivery
of anticancer drugs. Pharmaceutics 14 (8): 1566.
139 Jabir, N.R., Tabrez, S., Ashraf, G.M. et al. (2012). Nanotechnology-based approaches in anticancer
research. International Journal of Nanomedicine 4391–4408.

15 Nanodelivery of Food Polyphenols for Nutraceutical Applications
340
140 Kara, G., Calin, G.A., and Ozpolat, B. (2022). RNAi-based therapeutics and tumor targeted
delivery in cancer. Advanced Drug Delivery Reviews 182: 114113.
141 Kim, J., Li, S., Zhang, S., and Wang, J. (2022). Plant-derived exosome-like nanoparticles and their
therapeutic activities. Asian Journal of Pharmaceutical Sciences 17 (1): 53–69.
142 Pei, W., Li, X., Bi, R. et al. (2021). Exosome membrane-modified M2 macrophages targeted
nanomedicine: treatment for allergic asthma. Journal of Controlled Release 338: 253–267.
143 Sen, S., Xavier, J., Kumar, N. et al. (2023). Exosomes as natural nanocarrier-based drug delivery
system: recent insights and future perspectives. 3 Biotech 13 (3): 101.
144 El Khoury, D., Cuda, C., Luhovyy, B.L., and Anderson, G.H. (2012). Beta glucan: health benefits
in obesity and metabolic syndrome. Journal of Nutrition and Metabolism 2012.
145 Galanakis, C.M. (2021). Functionality of food components and emerging technologies. Foods 10
(1): 128.
146 Lordan, S., Ross, R.P., and Stanton, C. (2011). Marine bioactives as functional food ingredients:
potential to reduce the incidence of chronic diseases. Marine Drugs 9 (6): 1056–1100.
147 Qi, X., Tong, X., Pan, W. et al. (2021). Recent advances in polysaccharide-based adsorbents for
wastewater treatment. Journal of Cleaner Production 315: 128221.
148 Puttasiddaiah, R., Lakshminarayana, R., Somashekar, N.L. et al. (2022). Advances in
nanofabrication technology for nutraceuticals: new insights and future trends. Bioengineering 9
(9): 478.
149 Fathi, M., Donsi, F., and McClements, D.J. (2018). Protein‐based delivery systems for the
nanoencapsulation of food ingredients. Comprehensive Reviews in Food Science and Food Safety 17
(4): 920–936.
150 Gomes, A. and Sobral, P.J.D.A. (2021). Plant protein-based delivery systems: an emerging
approach for increasing the efficacy of lipophilic bioactive compounds. Molecules 27 (1): 60.
151 Detsi, A., Kavetsou, E., Kostopoulou, I. et al. (2020). Nanosystems for the encapsulation of natural
products: the case of chitosan biopolymer as a matrix. Pharmaceutics 12 (7): 669.
152 Malekzad, H., Mirshekari, H., Sahandi Zangabad, P. et al. (2018). Plant protein-based
hydrophobic fine and ultrafine carrier particles in drug delivery systems. Critical Reviews in
Biotechnology 38 (1): 47–67.
153 Mozafari, M.R., Flanagan, J., Matia‐Merino, L., et al. (2006). Recent trends in the lipid‐based
nanoencapsulation of antioxidants and their role in foods. Journal of the Science of Food and
Agriculture 86 (13): 2038–2045.
154 Hendawy, O.M. (2021). Nano-delivery systems for improving therapeutic efficiency of dietary
polyphenols. Alternative Therapies in Health & Medicine 27.
155 Mishra, Y., Amin, H.I.M., Mishra, V. et al. (2022). Application of nanotechnology to herbal
antioxidants as improved phytomedicine: an expanding horizon. Biomedicine & Pharmacotherapy
153: 113413.
156 Detoni, C.B., Souto, G.D., da Silva, A.L.M. et al. (2012). Photostability and skin penetration of
different e‐resveratrol‐loaded supramolecular structures. Photochemistry and Photobiology 88 (4):
913–921.
157 Sanna, V., Siddiqui, I.A., Sechi, M., & Mukhtar, H. (2013). Resveratrol-loaded nanoparticles based
on poly (epsilon-caprolactone) and poly (d, l-lactic-co-glycolic acid)–poly (ethylene glycol) blend
for prostate cancer treatment. Molecular Pharmaceutics 10 (10): 3871–3881.
158 Shao, J., Li, X., Lu, X. et al. (2009). Enhanced growth inhibition effect of resveratrol incorporated
into biodegradable nanoparticles against glioma cells is mediated by the induction of intracellular
reactive oxygen species levels. Colloids and Surfaces B: Biointerfaces 72 (1): 40–47.
159 Guo, L., Peng, Y., Yao, J. et al. (2010). Anticancer activity and molecular mechanism of
resveratrol–Bovine serum albumin nanoparticles on subcutaneously implanted human primary

References 341
ovarian carcinoma cells in Nude mice. Cancer Biotherapy & Radiopharmaceuticals 25 (4):
471–477.
160 Ranjan, A.P., Mukerjee, A., Helson, L. et al. (2013). Efficacy of liposomal curcumin in a human
pancreatic tumor xenograft model: inhibition of tumor growth and angiogenesis. Anticancer
Research 33 (9): 3603–3609.
161 Wang, D., Wang, T., Zhang, Z. et al. (2022). Recent advances in the effects of dietary polyphenols
on inflammation in vivo: potential molecular mechanisms, receptor targets, safety issues, and
uses of nano-delivery system and polyphenol polymers. Current Opinion in Food Science 100921.
162 Tang, J., Xu, N., Ji, H. et al. (2011). Eudragit nanoparticles containing genistein: formulation,
development, and bioavailability assessment. International Journal of Nanomedicine 2429–2435.
163 Zhang, H., Liu, G., Zeng, X. et al. (2015). Fabrication of genistein-loaded biodegradable TPGS-b-
PCL nanoparticles for improved therapeutic effects in cervical cancer cells. International Journal
of Nanomedicine 10: 2461.
164 Javed, Z., Khan, K., Herrera-Bravo, J. et al. (2021). Genistein as a regulator of signaling pathways
and microRNAs in different types of cancers. Cancer Cell International 21 (1): 1–12.
165 Dev, A., Sardoiwala, M.N., Kushwaha, A.C. et al. (2021). Genistein nanoformulation promotes
selective apoptosis in oral squamous cell carcinoma through repression of 3PK-EZH2 signalling
pathway. Phytomedicine 80: 153386.
166 Ju, J., Hong, J., Zhou, J.N. et al. (2005). Inhibition of intestinal tumorigenesis in Apc min/+ mice
by (−)-epigallocatechin-3-gallate, the major catechin in green tea. Cancer Research 65 (22):
10623–10631.
167 Gu, J.-W., Makey, K.L., Tucker, K.B. et al. (2013). EGCG, a major green tea catechin suppresses
breast tumor angiogenesis and growth via inhibiting the activation of HIF-1α and NFκB, and
VEGF expression. Vascular Cell 5: 1–10.
168 Shankar, S., Ganapathy, S., Hingorani, S.R., and Srivastava, R.K. (2008). EGCG inhibits growth,
invasion, angiogenesis and metastasis of pancreatic cancer. Frontiers in bioscience A Journal and
Virtual Library 13: 440–452.
169 Qian, Y.S., Ramamurthy, S., Candasamy, M. et al. (2016). Production, characterization and
evaluation of kaempferol nanosuspension for improving oral bioavailability. Current
Pharmaceutical Biotechnology 17 (6): 549–555.
170 Naeini, F., Namkhah, Z., Tutunchi, H. et al. (2021). Effects of naringenin supplementation in
overweight/obese patients with non-alcoholic fatty liver disease: study protocol for a randomized
double-blind clinical trial. Trials 22 (1): 1–9.
171 Ding, S.-M., Zhang, Z.H., Song, J. et al. (2014). Enhanced bioavailability of apigenin via
preparation of a carbon nanopowder solid dispersion. International Journal of Nanomedicine 9:
2327.
172 Telange, D.R., Patil, A.T., Pethe, A.M. et al. (2017). Formulation and characterization of an
apigenin-phospholipid phytosome (APLC) for improved solubility, in vivo bioavailability, and
antioxidant potential. European Journal of Pharmaceutical Sciences 108: 36–49.
173 Cochran, D.B., Gray, L.N., Anderson, K.W., and Dziubla, T.D.(2016). Degradable poly (apigenin)
polymer inhibits tumor cell adhesion to vascular endothelial cells. Journal of Biomedical
Materials Research Part B: Applied Biomaterials 104 (7): 1438–1447.
174 Adel, M., Zahmatkeshan, M., Akbarzadeh, A. et al. (2022). Chemotherapeutic effects of Apigenin
in breast cancer: preclinical evidence and molecular mechanisms; enhanced bioavailability by
nanoparticles. Biotechnology Reports e00730.
175 Chamcheu, J.C., Siddhiqui, I.A., Adhami, V.M. et al. (2018). Chitosan-based nanoformulated
(−)-epigallocatechin-3-gallate (EGCG) modulates human keratinocyte-induced responses and

15 Nanodelivery of Food Polyphenols for Nutraceutical Applications342
alleviates imiquimod-induced murine psoriasiform dermatitis. International Journal of
Nanomedicine 13: 4189.
176 Shan, Z., Nisar, M.F., Li, M. et al. (2021). Theaflavin chemistry and its health benefits. Oxidative
Medicine and Cellular Longevity 2021.
177 Hussain, Y., Mirzaei, S., Ashrafizadeh, M. et al. (2021). Quercetin and its nano-scale delivery
systems in prostate cancer therapy: paving the way for cancer elimination and reversing
chemoresistance. Cancers 13 (7): 1602.
178 Joshi, V., Tambat, S., Bhori, M. et al. (2022). Dietary Polyphenols in Bacterial and Fungal
Infections. Dietary Polyphenols in Human Diseases. 158–183. CRC Press.
179 Vieira, I.R.S. and Conte-Junior, C.A. (2022). Nano-delivery systems for food bioactive compounds
in cancer: prevention, therapy, and clinical applications. Critical Reviews in Food Science and
Nutrition 1–26.
180 Guo, C., Yin, J., and Chen, D. (2018). Co-encapsulation of curcumin and resveratrol into novel
nutraceutical hyalurosomes nano-food delivery system based on oligo-hyaluronic acid-curcumin
polymer. Carbohydrate Polymers 181: 1033–1037.
181 Piccolella, S., Crescente, G., Candela, L., and Pacifico, S. (2019). Nutraceutical polyphenols: new
analytical challenges and opportunities. Journal of Pharmaceutical and Biomedical Analysis 175:
112774.
182 Dini, I. and Grumetto, L. (2022). Recent advances in natural polyphenol research. Molecules 27
(24): 8777.
183 Ofosu, F.K., Daliri, E.B.M., Elahi, F. et al. (2020). New insights on the use of polyphenols as
natural preservatives and their emerging safety concerns. Frontiers in Sustainable Food Systems 4:
525810.
184 de Araújo, F.F., de Paulo Farias, D., Neri-Numa, I.A., and Pastore, G.M. (2021). Polyphenols and
their applications: an approach in food chemistry and innovation potential. Food Chemistry 338:
127535.