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Fucoxanthin activities motivate its nano/micro-

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Cite this: DOI: 10.1039/d0fo02176h

encapsulation for food or nutraceutical
application: a review
Chunyan Wang,a Xing Chen, *b Yoshimasa Nakamura, c
Chenxu Yu a,d
and
Hang Qi *a

Received 18th August 2020,
Accepted 21st October 2020
DOI: 10.1039/d0fo02176h
rsc.li/food-function
Fucoxanthin is a xanthophyll carotenoid abundant in marine brown algae. The potential therapeutic
effects of fucoxanthin on tumor intervention have been well documented, which have aroused great
interests in utilizing fucoxanthin in functional foods and nutraceuticals. However, the utilization of fucox-
anthin as a nutraceutical in food and nutrient supplements is currently limited due to its low water solubi-
lity, poor stability, and limited bioaccessibility. Nano/micro-encapsulation is a technology that can over-
come these challenges. A systematic review on the recent progresses in nano/micro-delivery systems to
encapsulate fucoxanthin in foods or nutraceuticals is warranted. This article starts with a brief introduction
of fucoxanthin and the challenges of oral delivery of fucoxanthin. Nano/micro-encapsulation technology
is then covered, including materials and strategies for constructing the delivery system. Finally, future pro-
spective has been discussed on properly designed oral delivery systems of fucoxanthin for managing
cancer. Natural edible materials such as whey protein, casein, zein, gelatin, and starch have been success-
fully utilized to fabricate lipid-based, gel-based, or emulsion-based delivery systems, molecular nano-
complexes, and biopolymer nanoparticles with the aid of advanced processing techniques, such as
freeze-drying, high pressure homogenization, sonication, anti-solvent precipitation, coacervation, ion
crosslinking, ionic gelation, emulsification, and enzymatic conjugation. These formulated nano/micro-
capsules have proven to be effective in stabilizing and enhancing the bioaccessibility of fucoxanthin. This
review will inspire a surge of multidisciplinary research in a broader community of foods and motivate
material scientists and researchers to focus on nano/micro-encapsulated fucoxanthin in order to facilitate
the commercialization of orally-deliverable tumor intervention products.

1. Introduction including ocular-protective, anti-obesity, and tumor intervention

Fucoxanthin is a natural pigment carotenoid, which is unique in
marine brown algae.1 Its structural formula is shown in Fig. 1,
including an unusual allenic bond, a 5,6-monoepoxide, and seven
conjugated double bonds. Similar to lutein, another popular caro-
tenoid from microalgae, fucoxanthin can give food an orange
color. In recent years, it has been shown that consuming fucox-
anthin-rich food is associated with multiple health benefits,
a
School of Food Science and Technology, Dalian Polytechnic University, National
Engineering Research Center of Seafood, Dalian 116034, P. R. China.
E-mail: xingchen@jiangnan.edu.cn; Tel: +86 510 85197367
b
State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi,
Jiangsu 214122, P.R. China. E-mail: qihang@dlpu.edu.cn; Fax: +86411 86323262;
Tel: +86411 86318785
c
Graduate School of Environmental and Life Science, Okayama University, Okayama,
Japan
d
Department of Agricultural and Biosystems Engineering, Iowa State University,
Ames, IA, USA
effects.2–4 However, due to the difficulty in achieving cost-effective-
ness in the production and extraction of fucoxanthin biomass, the
production of fucoxanthin from macroalgae or microalgae is
limited despite its high proportion in natural carotenoids.
Tumor is a major public health problem, with an estimated
9.6 million deaths in 2018 worldwide, in which, China
accounts for almost a quarter of the total.7 It has been esti-
mated that the number of worldwide tumor-related deaths will
increase to 11.4 million by 2030.8,9 Lung tumor and breast
tumor are the most common cancers, followed by prostate
tumor and colorectal tumor.7 Moreover, the most common
causes of death related to tumor are also lung tumor in men
and breast tumor in women. Tumor is a huge burden on
public health and economy around the world. One obvious
phenomenon is that the incidence rate and mortality rate of
tumor are relatively low in countries with advanced environ-
ment, economy, and healthcare.9 It was also confirmed by the
report of World Health Organization that Asia has the most

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Fig. 1 Fucoxanthin’s origin and its representative molecular structure and metabolism.
cancer patients and the highest case fatality rate, followed by
Europe and America. A notable trend in the past few decades
has seen a decline in tumors attributable to environmental
pollution in developed countries, while the opposite is true for
developing countries as industrialization and population
growth have brought more pollution exposure to people
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there.10 Prevention and early diagnosis and intervention has
been shown to be the most effective way of reducing tumor-
related deaths as most tumors have become treatable due to
the advancement of medical sciences.11
Diet plays an important role in tumor intervention and
treatment. The oral administration of nutraceuticals or func-
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tional foods containing bioactive ingredients could be instru-
mental in improving human physical or mental health, which
would in turn help with tumor intervention and treatment. For
this reason, there have been considerable efforts in the mining
of bioactive agents including carotenoids, polyphenols, flavo-
noids, essential fatty acids, peptides, and glucosinolates from
natural edible materials and incorporating them into foods,
nutrient supplements, and pharmaceuticals in the last
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tenoids, accounting for more than 10% of the estimated total
production of carotenoids on earth.16 This yellowish-brown
pigment exhibits a broad range of protective functionalities,
including anti-oxidant, anti-obesity, anti-diabetic, anti-cancer,
anti-inflammatory, hepato-protective, skin-protective, anti-
angiogenic, cerebrovascular, bone-protective, ocular-protective,
cardiovascular-protective, and anti-malarial activities.3 As a
xanthophyll carotenoid extracted from marine algae (Table 1),

decade.12–15 Fucoxanthin is the most abundant of natural caro- fucoxanthin is safe for animals and humans.17 Although fucox-

Table 1 Selected examples of fucoxanthin extraction and purification process from marine algae

Macroalgae/microalgae Extraction process Ref.

Laminaria japonica, Undaria
pinnatifida, Sargassum fusiforme
Phaeodactylum tricornutum
Isochrysis zhangjiangensis
Sargassum thunbergii
Nitzschia laevis
Phaeodactylum tricornutum
Fucus vesiculosus
Phaeodactylum tricornutum
Sargassum wightii Greville
Undaria pinnatifida
Phaeodactylum tricornutum
Chaetoceros gracilis
Nitzschia laevis
● The algae were first extracted using microwave-assisted extraction, then the Xiao et al., (2012)1
dried extract was dissolved and directly introduced into the high-speed
countercurrent chromatography system with a two-phase solvent system
consisting of hexane–ethyl acetate–ethanol–water (5 : 5 : 6 : 4, v/v/v/v).
● Fucoxanthin was isolated and structurally identified through Kim et al., (2012)17
chromatographic and spectroscopic methods, including 100% ethanol extracts,
LC-MS and HPLC analysis, isolation by silica gel chromatography, purification
by NMR, and quantification by reverse-phase high-performance liquid
chromatography.
● Lyophilized biomass was extracted with pure methanol. The methanol layer Li et al., (2019)113
was collected by centrifugation at 5000 rpm for 10 min. The extracts were
centrifuged for 15 min at 18 000 rpm before subjecting to high performance
liquid chromatography (HPLC) analysis.
● The powder was extracted three times with 90% methanol at 40 °C for 3 h, Wang et al., (2017)25
then purified by column chromatography with silica gel and further purified by
HPLC.
● The lyophilized powder was ground with liquid nitrogen. Ethanol was added Guo et al., (2019)24
to the ground cells for extraction, followed by shaking for 1 h. Supernatants
were collected by centrifugation. Extracts was obtained by evaporating with
nitrogen at 22 °C.
● Pigments were extracted from harvested cells by several methanol extractions Staleva-Musto et al.,
with brief (1.5 min) sonication. Crude pigment extracts were pooled, dried (2018)23
under vacuum, and dissolved in methanol for HPLC purification.
● Fucoxanthin extraction using enzymes (viscozyme), water, low-temperature Shannon & Abu-
(40 °C for 12 h) dehydration, and mechanical blending (optimum extraction Ghannam, (2018)114
parameters: enzyme-to-water ratio 0.52%, seaweed-to-water ratio 5.37%, and
enzyme incubation time 3.05 h).
● Fucoxanthin was extracted from the disrupted biomass by pressurized liquid Neumann et al.,
extraction for a static extraction time of 20 min at 100 °C and 100 bar using (2019)22
adequate subcritical organic solvents. Fucoxanthin was purified by multiple
separation steps using filters (0.25 µm) consisting of polytetrafluoroethylene to
a final purity of 99.2% (w/w) (HPLC).
● The dried powder was sequentially extracted with hexane and ethyl acetate Raji et al., (2020)29
for 6 h. The ethyl acetate extract was fractionated by silica column
chromatography to obtain fucoxanthin-rich fraction. The fraction was dissolved
in ethyl acetate, centrifuged to remove silica, and concentrated by the vacuum
rotary evaporator under reduced pressure to obtain fucoxanthin.
● Dried samples were ground into a fine powder and mixed with 75% (v/v) Liu et al., (2019)27
ethanol. After three extractions, the crude extracts were purified using
macroporous resins. Fucoxanthin was finally collected, concentrated in vacuo,
and then stored at −20 °C.
● Wet biomass was loaded into the mixing extraction vessel of the subcritical Aslanbay Guler et al.,
fluid extraction system and operated in the constant pressure mode to supply (2019)16
methanol with heating until the pressure was increased up to 20 MPa. The
extracted samples were collected and centrifuged at 6000 rpm for 10 min.
Fucoxanthin was finally collected after rotary evaporation.
● Freeze-dried algal samples was suspended in methanol and shaken overnight Peraman &
at about 100 rpm and filtered. The residues were re-extracted under the same Nachimuthu, (2019)28
conditions. The contents were stored for a period of 5 days at room temperature
(25 ± 2 °C) and then filtered. The solvent was removed under vacuum to
produce the dry crude extract.
● Fucoxanthin was determined by ultra-performance liquid chromatography Sun et al., (2018)20
coupled to photodiode array detector-quadrupole/travelling-wave ion mobility
mass spectrometry/time-of-flight mass spectrometry. Furthermore, solid-phase
extraction and thin-layer chromatography techniques were used to isolate and
purify fucoxanthinol and fucoxanthin from the extracts of N. laevis.

This journal is © The Royal Society of Chemistry 2020 Food Funct.


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anthin can be produced by both macroalgae and microalgae,
including Laminaria japonica, Undaria pinnatifida, and
Sargassam fusiforme, as well as Phaeodactylum tricornutum,
Odontella aurita, Isochrysis galbana, and Nitzschia laevis,18–21
which is much richer in some microalgae, such as
Phaeodactylum tricornutum.22 In the same line, the production
of fucoxanthin from microalgae is economically feasible due
to the advantages of high fucoxanthin content and extraction
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efficiency with a short growth cycle.23,24 Furthermore, micro-
algae could be cultivated in bioreactors with a high propa-
gation rate and good control.17 Table 1 shows several kinds of
extraction methods for fucoxanthin from different marine
algae. The unique allenic bond structure of fucoxanthin is
unstable and can be easily damaged by heating, aerial
exposure, or illumination.25 However, it is the structure of
allenic bond in fucoxanthin that gives it anti-oxidative, anti-
inflammatory, anti-obesity, selective bacteriostasis, and anti-
cancer activities.22,26–29
Despite the potential health benefits of fucoxanthin, its
utilization as a nutraceutical ingredient by the food and nutra-
ceutical industry is currently limited due to its poor stability
and low bioaccessibility caused by aqueous insolubility. All of
these characteristics are interrelated and associated with
fucoxanthin’s molecular hydrophobicity, unstable chemical
structure, and its low release from food substrates or their
complexes.22,30
When it is difficult to directly introduce functional ingredi-
ents into food, nano/micro-encapsulation-based approaches,
in which nanocarriers are utilized as delivery systems, could be
sought as alternatives. In recent years, several kinds of nano-
carriers have been developed to encapsulate, protect, trans-
port, and eventually release fucoxanthin, and to overcome
some of the limitations currently compromising fucoxanthin
utilization.5,31–34 To date, relevant discussions on fucoxanthin
mostly center on its bioactivity related to human health or the
benefits of its direct oral administration (including combined
use with other drugs) to human health.35,36 There is no com-
prehensive review on how the bioaccessibility issue can be
addressed to improve the functional bioactivity of fucoxanthin
with nano/micro-encapsulation approaches. This review is
aimed at filling this void. The challenges of fucoxanthin deliv-
ery are discussed as well as the current knowledge on utilizing
nano/micro-encapsulation in order to enhance its bioaccessi-
bility. Furthermore, future trends regarding the nano/micro-
encapsulation systems of fucaxanthin and their potential use
as a tumor intervention ingredient in functional foods, nutra-
ceuticals, or nutrient supplements are prospected.
2. Tumor intervention efficacy of
fucoxanthin
2.1. Metabolism of fucoxanthin
The digestion, absorption, and transportation of fucoxanthin
is a systemic and complicated course. As a hydrophobic and
lipid-soluble carotenoid, ingested fucoxanthin should be
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released from the food matrix to be incorporated into mixed
lipid micelles.37,38 Meanwhile, fucoxanthin can be hydrolyzed
into fucoxanthinol (Fig. 1) in the gastrointestinal tract and is
further converted into amarouciaxanthin A (Fig. 1) in the
liver.39,40 Similar to the other carotenoids, the absorption of
fucoxanthin may also occur in the intestinal mucosal epithelial
cells from the proximal half of the small intestine through the
facilitated diffusion of scavenger receptor B1 (SR-B1).41,42
However, pharmacokinetic studies have showed that after
fucoxanthin administration (a single oral dose of 31 mg or
6.1 mg day−1 for a week), only fucoxanthinol was found in the
circulation of human bodies, while both fucoxanthinol and
amarouciaxanthin A were found in the plasma and other
tissues of mice.43,44 It demonstrated that the metabolic rate of
fucoxanthin in mice was faster than that in humans, which
should be considered when conducting studies for the biologi-
cal activities of fucoxanthin in mice. It was recently found that
degradation components (apo-13-fucoxanthinone and apo-9′-
fucoxanthinone) of fucoxanthin obtained by ozonolysis had
the same anti-proliferative effect against Caco-2 cells as fucox-
anthin itself as long as the allene structure remained intact.45
Moreover, fucoxanthin seemed to exert its biological effect in
different tissues as different forms of metabolites. For
instance, after the administration of dietary fucoxanthin sup-
plementation (including: 160 nmol as a single oral dose,
160 nmol day−1 for a week, and 128 nmol day−1 for 14 days) in
mice, fucoxanthinol and amarouciaxanthin A but not fucox-
anthin were found in the plasma and different tissues.40,43,44
It is clear that oral fucoxanthin is easy to degrade in the
stomach and thus lose its biological activity, or be hydrolyzed
to produce key functional derivatives that can be absorbed by
the small intestine, thus entering the liver metabolism and
blood circulation system to play an anti-cancer role. But such a
direct oral administration of pure free fucoxanthin may lead to
a reduced absorption rate due to its degradation in the diges-
tive tract; and eating kelp may also have a low absorption rate
due to its low fucoxanthin content (compared with pure fucox-
anthin), which seriously restricts the tumor intervention
efficacy of diet fucoxanthin.
2.2. Tumor intervention efficacy
The tumor intervention efficacy of fucoxanthin has been
reported in various tumor models.35 Fig. 2 shows several
reported mechanistic pathways for the tumor intervention
efficacy of fucoxanthin. Fucoxanthin can exert effects on cell
cycle arrest and apoptosis, which are related to tumor interven-
tion and treatment.46 Moreover, fucoxanthin is an anti-angio-
genic agent, which could suppress the expression of pro-angio-
genic factor (FGF-2), trans-activation factor, and their receptor,
hence contributing to the inhibition of tumor metastasis.47,48
Hereby, different regulatory and protective mechanisms or
related signal transduction pathways of fucoxanthin and its
metabolites are discussed in detail.
Fucoxanthin and, to a greater extent, its metabolite fucox-
anthinol, have been shown to reduce the cell viability or
inhibit cell proliferation by inducing cell cycle arrest in human
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Fig. 2 Several reported mechanistic pathways of the tumor intervention efficacy of fucoxanthin.
skin tumor cells (B16-F10),49 human osteosarcoma cells (Saos-
2, LM8, and 143B),50 human primary effusion lymphoma
cells,51 human gastric adenocarcinoma cells (SGC-7901 and
BGC-823),52 human liver tumor cells (HepG2),46 human non-
small cell lung tumor cells (A549 and H1299),53 human colon
adenocarcinoma cells (DLD-1, Caco-2 and HT-29),54 human
prostate cancer cells (LNCaP, PC-3 and DU 145),55 and human
bladder cancer cells (T24).56 The inductive effect of fucox-
anthin on cell cycle arrest was mediated by increased
expressions of cyclin-dependent kinase-inhibitory protein
( p21), and decreased expressions of cyclin-dependent kinase-4
and cyclin Ein human osteosarcoma and bladder tumor cells.
It could also increase gap junction intercellular communi-
cation between the tumor cells, which could then result in
increased intracellular signaling, leading to cell cycle arrest
and apoptosis.46,50
In fact, fucoxanthin and its metabolites could induce the
apoptosis of cells by reducing the expression of anti-apoptotic
protein (Bcl-2, Bcl-xL, XIAP, and survivin), anti-apoptotic tran-
scription factor (signal transducer and activator of transcrip-
tion 3, STAT3), and their phosphorylated active forms, while
increasing the expression of pro-apoptotic protein (Bax) and
activating the caspases family (caspases-3, -8, and -9) in
human cancer cells, which has been discovered so far in
human glioma tumor cells (U87 and U251),57 human gastric
adenocarcinoma cells (SGC-7901 and BGC-823),52 human liver
tumor cells (HepG2),46 human non-small cell lung tumor cells
(A549 and H1299),53 human colon cells (Caco-2),58 human
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bladder tumor cell line cells (T24),56 and human cervical
tumor cells (SiHa).59 Fucoxanthin and fucoxanthinol can also
suppress angiogenesis in embryo blood vessels. Fucoxanthin
at concentrations over 10 µM was shown to inhibit the prolifer-
ation and tube formation of human umbilical vein endothelial
cells, and fucoxanthin in the concentration range of 10–20 µM
could also inhibit the differentiation of endothelial progenitor
cells into endothelial cells, which was associated with new
blood vessel formation in the tumor.60 Furthermore, studies
have shown that fucoxanthin could inhibit the proliferation of
murine astroglioma cells by inhibiting the expression of angio-
genic indicators such as vascular endothelial growth factor
and epidermal growth factor receptor.47,48
In addition, the inhibitory effect of fucoxanthin on the
migration or invasion of tumor cells might be related to its
anti-angiogenic activity. A previous study has shown that fucox-
anthin could down-regulate the phosphorylation of FGF-2
caused by extracellular signal-regulated kinase and protein
kinase B in endothelial cells.48 Moreover, fucoxanthin could
suppress the migration of human glioma tumor cells by redu-
cing the expression of matrix metalloproteinases 2 and −9,
which play vital roles in tumor invasion and metastasis.57
Consistently, fucoxanthin has been found to reduce the
migration and invasion of melanoma cells (B16-F10) in mice
by reducing the expression of matrix metalloproteinases 9.61
Therefore, fucoxanthin and fucoxanthinol could be effective in
tumor intervention and management. However, there are still
some serious challenges such as how to stably and efficiently
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deliver fucoxanthin to the tumor site and then exert its anti-
cancer activity.
3. Challenges in the oral delivery of
fucoxanthin
The annual production of fucoxanthin from brown algae and
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microalgae is on the rise, and its potential utilization as a
tumor nutraceutical and/or preventive agent is getting more
and more attention from the food and pharmaceutical indus-
tries.17 Oral administration of free fucoxanthin is not effective
due to its poor solubility and gastrointestinal stability, leading
to its reduced bioaccessibility.43,45 Moreover, the processing
and storage instability of fucoxanthin tends to influence its
utilization in functional foods and nutraceuticals as well.62
3.1. Instability
The issues of instability of fucoxanthin can be analyzed from
two aspects—processing and storage instability, and gastroin-
testinal digestion instability. As previously mentioned, the
unique allenic bond structure of the fucoxanthin molecule is
unstable and could be easily damaged by heating as well as
oxygen, acid, and light exposure,17,25 which makes fucoxanthin
susceptible to unfavorable environmental exposures. Fung,
Hamid, and Lu (2013)63 found that the fucoxanthin content
and anti-oxidant activity of processed (rinsing, cutting, blanch-
ing, salting, and oven drying) Undaria pinnatifida were lower
than that of the freeze-dried unprocessed ones. It was reported
that with the increase in temperature (2 °C, 10 °C, 26 °C), the
stability of fucoxanthin in water decreased significantly, i.e.,
after 4 weeks of storage at 26 °C, the content of fucoxanthin in
water degraded to about 30% of the initial amount, indicating
the instability of fucoxanthin in water.5 Moreover, fucoxanthin
may also interact with other components of the food matrix,
which could also alter its stability. For example, fucoxanthin is
prone to degradation in the food matrix containing transition
metals, while it is more stable in a food matrix containing
milk protein.64–66 As we already discussed, the metabolism
and biotransformation of fucoxanthin released from the food
matrix mainly occurs in the gastrointestinal tract and the liver
after hydrolysis, dehydrogenation, and isomerization.37,38,67 In
the gastrointestinal environment, fucoxanthin is extremely sus-
ceptible to degradation or transformation. The acidic environ-
ment in the stomach and the cholesterol esterase and lipase
located in the gut play key roles in the degradation and bio-
transformation of fucoxanthin. Since the bioaccessibility and
potential protective effects of fucoxanthin are dependent on its
physical and chemical structure, they could change notably
after metabolic transformation.41,42
3.2. Insolubility and low bioaccessibility/bioavailability
The bioaccessibility of the ingested bioactive compound is
evaluated based on the ease of its release from the food matrix
and subsequent absorption through the digestive tract. The
bioavailability of the ingested bioactive compound is evaluated
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based on its digestion, absorption, metabolism, distribution,
and bioactivity.5 The evaluation of bioaccessibility is usually
done in a simulated gastrointestinal digestion model in vitro
that is relatively simple, inexpensive, and repeatable.68–71 The
evaluation of bioaccessibility and bioavailability of fucoxanthin
is helpful to understand the interaction between fucoxanthin
and food components, and the effects of pH, enzymes, and
food processing on its absorption rate or absorption poten-
tial.62 Fucoxanthin, as a non-polar and hydrophobic marine
phytochemical, is not water soluble, which leads to its low
bioaccessibility. In fact, fucoxanthin can form aggregates by
intermolecular bonding due to the thermodynamic inaccessi-
bility between its non-polar groups and water.72 The bioacces-
sibility of fucoxanthin may be influenced by the food matrix
and the gut microbiota composition based on various diets.26
For instance, fucoxanthin may bind to proteins or dietary
fibers in the food matrix and be decomposed and utilized by
some intestinal microorganisms, which may be excreted via
faeces, thus reducing the bioaccessibility of fucoxanthin in
gastrointestinal fluids.26,73 Moreover, fucoxanthin can promote
the growth of Escherichia coli and Lactobacilli, the main micro-
organisms in the gut, and can be deacetylated by these two
microorganisms in turn to produce fucoxanthinol, which may
increase its bioaccessibility.27 For tumor patients, their diges-
tive tract could be affected by the tumor so that the digestion,
metabolism, absorption, and biodistribution of fucoxanthin
could be changed, and the intestinal flora related to fucox-
anthin metabolism could be disordered as well, thus affecting
its bioaccessibility.5,27 In addition, the transportation and
absorption of the ingested fucoxanthin may be mediated
through the facilitated diffusion of SR-B1 in the intestinal
tract.41 Hence, the absorption rate of fucoxanthin in the intes-
tinal epithelium cells could also influence the bioaccessibility
of fucoxanthin, which may in turn cause a difference of its
effective concentration of fucoxanthin in the circulatory
system, thus affecting its ultimate protective effects. Although
not proven, some possible hydrophilic metabolites of fucox-
anthin produced during biotransformation may be excreted
with urine, reducing the effective concentration of fucoxanthin
in the target tissues.42 Such types of biotransformation are
more likely to occur during the oral administration of fucox-
anthin and further lower its bioaccessibility.
4. Nano/micro-encapsulation
technology for fucoxanthin (Table 2)
In recent decades, the application of encapsulation technology
to enhance the stability, solubility, and bioaccessibility of bio-
active compounds has seen an exponential growth, fueled by
the rapid progress of key enabling technologies such as micro-
nano technology, industrial biotechnology, advanced
materials, and advanced manufacturing technologies. Silva
et al. (2017)74 found that the water solubility of lutein and its
efficacy in improving murine declarative memory were
increased by PVP nanoparticle delivery systems, which were
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Table 2 Encapsulation systems of fucoxanthin

Application Encapsulation Encapsulation

fields Encapsulation materials system techniques Results Ref.

Food Casein/chitosan Biopolymer Freeze drying and Improved bioavailability of Koo et al.,
nanoparticles ionic gelation fucoxanthin (2016)5
Food Zein/caseinate Biopolymer Anti-solvent Improved stability, bioaccessibility, Li et al.,
nanoparticles precipitation anti-oxidant activity, and anti- (2018)30
proliferative activity of fucoxanthin
Food Gum arabic/gelatin/ Gel-based delivery Freeze drying Improved gastrointestinal stability Li et al.,
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alginate hydrogel system and oral efficacy of fucoxanthin (2019)21

Food Medium-chain o/w nanoemulsion- High pressure Improved stability and Ma et al.,
triacylglycerol/whey based delivery homogenization bioaccessibility of fucoxanthin (2019)33
protein isolate system
Food Medium-chain o/w Microchannel Improved chemical stability and Ma et al.,
triacylglycerol/whey microemulsion- emulsification sustained release of fucoxanthin (2020)93
protein isolate/modified based delivery
lecithin/Tw20 system
Food Seaweed oil/sunflower o/w nanoemulsion- Ultrasound-assisted Improved encapsulation efficiency Saravana et al.
oil/κ-carrageenan based delivery emulsification (98.99%), stability, and (2019)108
system bioaccessibility of fucoxanthin, and
good cell inhibition against a few
cancer cell lines
Food Porous starch/ Molecular Solvent exchange/ Improved the storage stability of Oliyaei et al.,
maltodextrin/gum arabic nanocomplexes freeze drying/vacuum fucoxanthin (2020)86
drying
Food Whey protein isolate/ Molecular Complex coacervation Improved the storage and simulated Zhu et al.,
lysozyme nanocomplexes gastrointestinal stability of (2019)78
fucoxanthin
Food Whey proteins Molecular Molecular self- Improved The stability and water Zhu et al.,
nanocomplexes assembly solubility of fucoxanthin (2017)32
Food Cetylpalmitate-based Lipid-based Ultrasonic and freeze Improved stability and sustained Quan et al.,
solid lipid core and fish delivery system drying release of fucoxanthin (2013)85
gelatin–gum arabic
coacervate shell
Food Chitosan/glycolipid Gel-based delivery Ionic gelation and Improved stability, bioaccessibility, Ravi &
system freeze drying and anti-tumor activity of Baskaran,
fucoxanthin (2015);31 Ravi
et al., (2018)58
Cosmetics Self-emulsifying wax/ Lipid-based High pressure Improved stability and Tavares et al.,
liquid polymer/UV filters delivery system homogenization and photoprotective potential of (2020)82
emulsification sunscreens
Food and Palm stearin/fish gelatin/ Lipid-based Ultrasonic, Improved the storage stability and Wang et al.,
drugs gum arabic delivery system emulsification and sustained release of fucoxanthin (2017)25
freeze drying

prepared using solvent evaporation. Chen et al. (2019)71 con-
structed zein/carrageenan core–shell nanoparticles based on
an anti-solvent precipitation method, which enhanced the
bioaccessibility and provided excellent protection through cur-
cumin against simulated gastrointestinal environments. Liu
et al. (2018)75 successfully prepared β-lactoglobulin/chitosan
oligosaccharides nanocomplexes by spontaneous co-assembly
and freeze-drying to improve the stability and anti-oxidant
activity of astaxanthin with high effectiveness. All these reports
suggested that suitable encapsulation systems could be essen-
tial to improve the bioaccessibility and thereby the in vivo
efficacy of fucoxanthin. With a reliable encapsulation system,
fucoxanthin can be delivered to the target without losing its
active structure in the process of product manufacturing,
transport and storage, as well as metabolism and
biotransformation.5
In general, the nano/micro-encapsulation of a hydrophobic
bioactive compound such as fucoxanthin is usually carried out
due to the following reasons: (1) to preserve the physical struc-
ture of the entrapped compound; (2) to facilitate the incorpor-
ation of multiple mutually incompatible compounds; (3) to
protect the bioactive compound from being degraded by
environmental factors such as sunlight, oxygen, and heat; (4)
to increase the bioaccessibility of the bioactive compound; (5)
to control the rate or location of the release of the bioactive
compound.76,77 Apart from functional food applications,
nanoencapsulated products are also widely used in pharma-
ceuticals, cosmetics, healthcare, and other related industries.
4.1. Natural materials for fucoxanthin nano/micro-
encapsulation
The encapsulating material plays an important role in the
efficiency of entrapping fucoxanthin. Various materials, such
as semiconductor, inorganic salts, as well as artificial and
natural polymers, have been explored as nanoencapsulating
carriers in a series of ordered and delicate bottom-up nano/
micro-encapsulation methods.4,34,78 Among them, edible col-
loids and polymers from natural materials have been gaining

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Review Food & Function

popularity, especially in the food sector, due to strict regulat-
ory requirements. Proteins and polysaccharides, including
whey protein, casein, zein, alginate, chitosan, gum arabic, and
gelatin, have been confirmed as safe nanoencapsulating car-
riers for fucoxanthin for improving its bioaccessibility.79 The
best performing ones are discussed in detail below.
Whey protein. Nowadays, there is a considerable interest in
the application of whey protein for the encapsulation and con-
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by Trp213, Leu237, Val240, Leu259, Ala260, and Ala290 of BSA
(Fig. 3A and D). Fucoxanthin could also bind to the top of the
calyx of β-Lg through van der Waals force, hydrogen bond
(Asp28), and hydrophobic force (Leu31, Pro38, Ile71, Ile72,
Ile84) (Fig. 3B and E). In the case of α-La, residues of Phe31,
Tyr36, Ile41, Val42, and Trp118 were shown to be involved in
the formation of α-La-fucoxanthin nanocomplex mainly via
hydrophobic interaction (Fig. 3C and F). The binding affinities

trolled release of fucoxanthin. Whey protein ( particularly, the
whey protein isolate, WPI) extracted from milk is well known
for its high nutritional value and ease of digestion and absorp-
tion. It is one of the most widely commercialized high-quality
protein supplements for humans, containing bovine serum
albumin (BSA), β-lactoglobulin (β-Lg), α-lactoalbumin (α-La),
lactoferrin, immunoglobulin, and many other active ingredi-
ents. WPI is also widely used in food, pharmaceutical, and
other industries due to its various physiological functions.4,80
In addition to its nutritional value, whey proteins can also
serve as important transporters in the body, which are involved
in the absorption and transport of a variety of small molecule
nutrients and amino acids in cells.81 The existence of hydro-
phobic cavities in whey protein molecules makes WPI a good
nano-carrier for hydrophobic nutrients.79 Nanocomplexes of
fucoxanthin binding to BSA, β-Lg, and α-La have been success-
fully constructed and characterized (diameter size < 300 nm).32
Molecular docking results suggested that fucoxanthin mole-
cules can bind tightly to the Sudlow sites I of BSA where they
form hydrogen bonds with the Tyr149 and Arg256 residues of
BSA, and interacted with the hydrophobic pocket constituted
of various WPI components to fucoxanthin showed a decreas-
ing order as BSA > β-Lg > α-La. In another report, nanocom-
plexes composed of fucoxanthin, oleic acid, and BSA were
created and characterized by Liu et al. (2019).4 According to
their results, fucoxanthin molecules were bound at the sites of
the hydrophobic cavity of BSA with amino acid residues
183–291 through intermolecular π–π interactions, van der
Waals forces, and hydrogen bonds, while oleic acid was bound
at the region of amino acid residues 115–185 through van der
Waals forces. Fucoxanthin and oleic acid were bound to BSA at
completely different sites, while the presence of oleic acid
could strengthen the bonding of fucoxanthin to the hydro-
phobic cavities of the BSA. As a conclusion, WPI could be
effectively utilized to encapsulate fucoxanthin in food systems.
Casein. As a major protein family in milk, caseins also
demonstrated the same ligand binding properties as well as
the self-assembly ability as that of WPI. The potential of casein
micelles as a delivery system for bioactive compounds and
nutraceuticals has been showcased in either self-assembled
micelles from casein fractions (mostly β-casein) or reas-
sembled micelles from commercial caseins (caseinates), which

Fig. 3 TEM photographs and molecular docking of fucoxanthin into BSA (A), β-Lg (B), and a-La (C). [BSA] = [β-Lg] = [α-La] = 5 mM, [fucoxanthin] =
15 mM. The magnification of TEM photographs is 300 000 in BSA, 400 000 in β-Lg, and 200 000 in α-La. For molecular docking, whey proteins are
showed as cartoon colored in cyan (helix), magenta (sheet), and salmon (loop). The spherical model displays fucoxanthin colored as orange. Details
of protein residues interacting with fucoxanthin in BSA (D), β-Lg (E), and a-La (F) are also shown. The stick models represent fucoxanthin and key
amino acid residues, colored as orange and green, respectively. Dashed line colored as yellow shows the hydrogen bond (reproduced with per-
mission from Zhu et al., 2017;32 refer to this text for more details).

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Food & Function
can protect the entrapped substances against environmentally
induced degradation and oxidation.82,83 The unique properties
of caseins and the casein micelles, and how these properties
can enhance the successful delivery of sensitive ingredients
and bioactives, have been well covered in a previous review.83 A
recent study has showed that casein could be combined with
chitosan to generate fucoxanthin-loaded nanoparticles.5 The
casein-based nanoparticles were mixed micelles and vesicles
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containing fucoxanthin in the micelle phases, and fucoxanthin
could be released more easily from the matrices, resulting in
better fucoxanthin bioaccessibility compared to the free ones.
In addition, due to the increase in the adsorption capacity of
chitosan to mucin, the chitosan coated casein-based nano-
particles had a higher accumulation of fucoxanthinol in the
blood circulation of C57BL/6 mice. As a conclusion, caseins
could also be effectively facilitated to serve as fucoxanthin car-
riers in order to enhance its water solubility and
bioaccessibility.
Zein. Zein, a protein derived from maize seeds (Zea mays L.),
has been approved for oral use by the US Food and Drug
Administration (FDA). Due to its inherent hydrophobicity, zein
can self-assemble into a variety of structures through a simple
process commonly known as anti-solvent precipitation.
Besides, zein is resistant to digestive enzymes in the gastroin-
testinal tract and zein colloidal particles can deliver a con-
trolled release of functional components loaded in them.
These characteristics have made zein a great candidate to
generate encapsulating carriers for a variety of bioactive com-
pounds.84 Fucoxanthin-loaded zein/caseinate nanoparticles
have been successfully fabricated where zein interacted with
fucoxanthin through hydrophobic interactions.30 The obtained
nanoparticles were stabilized by caseinate; they greatly
improved the anti-cancer activity and bioaccessibility of the
encapsulated fucoxanthin.
Gelatin and gum arabic. Gelatin and gum arabic, two oppo-
sitely charged biopolymers, are safe, biocompatible, and abun-
dant. Both of them could be co-assembled by complex coacer-
vation to encapsulate hydrophobic bioactive compounds such
as fucoxanthin.85 It has been reported that gelatin–arabic gum
microcapsules, as a protective shell, could reduce the contact
of fucoxanthin with light, oxygen, heat, and other degrading
factors, and enhance the dispersibility of this insoluble ingre-
dient in water so as to improve its stability in food systems and
promote its effective oral delivery to the target tissue.85
However, this microcapsule shell composed of gelatin and
gum arabic is unstable in the stomach. In the presence of
pepsin and gastric acid, the shell protein is prone to hydrolysis
and protonation, resulting in the breaking of the hydrogen
bond and the weakening of electrostatic adsorption between
the protein and the polysaccharide.21 Therefore, when the
microcapsules are used for the oral delivery of fucoxanthin,
some of these encapsulated active ingredients could be
released directly into the stomach due to the swelling and dis-
integration of the capsules in the gastric environment.
Consequently, the target release amount of fucoxanthin in the
small intestine and its absorption and utilization in the target
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cells is reduced.85 These shortcomings severely limit the tra-
ditional application of gelatin/gum arabic microcapsule-based
carriers for the oral delivery of various functional active ingre-
dients. To solve such problems, a novel delivery system fabri-
cated by the complex coacervation of gelatin/gum arabic micro-
capsules and alginate hydrogel beads has been developed as
specialized oral vehicles of fucoxanthin. The results of simu-
lated gastrointestinal digestion in vitro indicated that the
obtained beads could protect fucoxanthin while being incu-
bated in simulated gastric fluid and the amount of fucox-
anthin released in the simulated intestinal fluid was more
than 90%. In vivo experiments on mice have shown that the
encapsulated fucoxanthin could more effectively lower the
blood lipid and oxidative stress level compared to the free
ones.21
Porous starch. Porous starch is a new type of modified
starch with a honeycomb structure. After natural raw starch is
hydrolyzed, small pores (about 1 µm in diameter) are formed
on the surfaces of the starch granules. These small pores
extend to the inside of the granules, which can then entrap
various substances in them. In porous starch, the porosity
accounts for about 50% of the particle volume. Thus, the
porous starch particles have a good carrying capacity and can
be used as a new type of organic embedding material for the
encapsulation of various functional active ingredients. For
fucoxanthin, porous starch carriers are on the rise because of
their large pore size, high specific surface area, and ease of
synthesis.86 Oliyaei et al. (2020)86 produced a fucoxanthin-
loaded delivery system based on porous starch, maltodextrin,
and gum arabic by using methods of solvent exchange and
freeze drying. According to the results, the storage stability
and the anti-oxidant/anti-proliferative activities of fucoxanthin
were greatly improved by this porous starch-based delivery
system. Oliyaei et al. (2020)34 developed a new and original
encapsulation system for fucoxanthin (encapsulation efficiency
up to 94.05%). Porous starch and halloysite nanotubes were
combined via solvent exchange and vacuum hybrid to improve
the stability and sustained release of fucoxanthin, and a
release rate of 27.09 ± 0.17% of fucoxanthin in 6 h was
achieved by the simulated digestive fluids in vitro. Nowadays,
with the rapid development of colloidal/polymer science and
nanotechnology, more nano-encapsulation materials are con-
stantly being developed to fully take advantage of the potential
health benefit of fucoxanthin so as to produce functional
foods and pharmaceuticals, especially for the prevention and
treatment of chronic diseases such as tumor.
4.2. Types of delivery systems for nanoencapsulated
fucoxanthin
Various delivery systems for nanoencapsulated fucoxanthin
have been developed to cope with different encapsulation
materials and to meet specific needs. The interactions
between fucoxanthin and the encapsulated material play sig-
nificant roles in determining the performance of the delivery
system applied in functional foods and nutraceuticals.
Fucoxanthin can interact with encapsulation materials both
Food Funct.

Review
covalently to form conjugation bonds and non-covalently via
hydrogen bond, hydrophobic interaction, electrostatic inter-
action, and van der Waals forces.32,72,78 Based on the encapsu-
lation materials and mechanisms, various delivery systems, as
summarized in Fig. 4, including lipid-based delivery systems,
gel-based delivery systems, emulsion-based delivery systems,
molecular nanocomplexes, and biopolymer nanoparticles,
have been studied and developed in order to increase the solu-
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bility of fucoxanthin in water, and thus, to improve its
bioaccessibility.5,31,33,58
Lipid-based delivery systems. As the commonly used delivery
system for lipophilic active substances, lipid-based delivery
systems include liposomes and solid lipid cores. Liposomes
have been widely used in the pharmaceutical and cosmetic
industries to improve chemical solubility and to facilitate con-
tinuous targeted material delivery with improved protective
effects and reduced chemical resistance.87 Liposomes, as the
name suggests, are mainly composed of lipids, including phos-
pholipids and cholesterol.88 The size distribution of liposomes
is wide, from tens of nanometers to several microns. The
surface of liposomes is usually coated with a layer of 4–5 nm
hydrophilic membrane. Hydrogen bonding and van der Waals
interactions are the main driving forces in the formation of
liposomes. The formation and function of liposome as a deliv-
ery system for lipophilic and hydrophilic functional com-
ponents have been fully discussed in previous reviews.89,90 It
was suggested that soybean lecithin can be used to prepare
fucoxanthin-loaded soybean phosphatidylcholine-liposomes,
which could effectively improve the anti-oxidant and tumor
intervention efficacy of the delivered fucoxanthin compared to
that of the free one when administered orally.91,92 However,
due to the low loading capacity, the stimulation of the human
digestive tract caused by a large amount of surfactants, and
the possible leakage of active ingredients during storage, the
application of liposomes in foods is quite limited.92 To over-
come these shortcomings, several technologies have been
studied. Quan et al. (2013)85 fabricated fucoxanthin-loaded
microspheres using cetylpalmitate solid lipid core coated with
fish gelatin–gum arabic coacervate shell, which exhibited a
greatly enhanced stability and sustained release of fucoxanthin
under simulated gastrointestinal conditions. Wang et al.
(2017)25 constructed fucoxanthin-loaded microcapsules with
palm stearin as the solid lipid core and fish gelatin–gum
arabic complex coacervates as the protective coverings, which
also exhibited improved stability against light, humidity, and
temperature, and a sustained release of fucoxanthin under
simulated gastrointestinal condition. The encapsulation
efficiency and loading capacity reported for fucoxanthin were
98.3% and 0.04%, respectively, in this system. The images of
optical microscopy and scanning electron microscopy reveal
that the obtained microcapsules have smooth surfaces with a
mean diameter of 19.19 µm. Although the biopolymer-coated
solid lipid cores in these systems could better protect fucox-
anthin against light, heat, and simulated gastrointestinal
environment compared to the liposomes, the low loading
capacity still limits its widespread use in the industry.
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Food & Function
Gel-based delivery systems. The nanogel delivery system for
the encapsulation of fucoxanthin could be constructed by
using ionic gelation method through ionic interaction between
two kinds of oppositely charged embedded materials in the
presence of ions.21,71 Spherically cross-linked hydrophilic
polymer-based nanogel beads could be made with this
method, in which the stable embedding of active substances
could be achieved.21 Ravi & Baskaran (2015)31 encapsulated
fucoxanthin using chitosan and glycolipid by the ionic gela-
tion of sodium tripolyphosphate. The smooth spherical gel
beads (200–550 nm) were characterized by scanning electron
microscopy and dynamic light scattering analyses. The yield,
encapsulation efficiency, and loading capacity of the nanogel
beads were 70%, 90%, and 47%, respectively. Based on the
zeta potential analysis, fucoxanthin-loaded nanogel beads with
glycolipid (+30 to +50 mV) were more stable than that of the
ones without glycolipid (+15 mV). The release of fucoxanthin
from these beads was controlled by the swelling and relaxation
of the beads in the simulated digestive juice, while the stabi-
lity, bioaccessibility, and anti-tumor activity of fucoxanthin
were all improved by the nano/micro-encapsulation.58 Li et al.
(2019)21 synthesized complex nanocarriers containing gum
arabic–gelatin microcapsules and calcium-crosslinked alginate
hydrogel beads to improve the gastrointestinal stability and
oral efficacy of fucoxanthin. The obtained composite nanogel
beads exhibited a uniform spherical shape and a brownish-
yellow color arose from the loaded fucoxanthin, which was dis-
tributed uniformly in the microcapsule core instead of being
cross-linked to the gel shell. The gel-based approach could be
applied to produce various delivery vectors from different
encapsulation materials by selecting suitable conditions.58
However, the gelation process usually takes a long time, which
may result in a large number of pores in the gel beads due to
the escape of gas and organic compounds, which may lead to
gel shrinkage in the subsequent drying step.21
Emulsion-based delivery systems. Previous studies have
demonstrated that emulsion-based delivery systems can
improve the bioaccessibility of fucoxanthin compared to direct
administration.33 Table 2 shows in detail the nano/micro-
emulsion of fucoxanthin encapsulation that was fabricated.
They are used in the pharmaceutical and cosmetic industries,
which refer to emulsion systems with nanoscale dimensions,
typically smaller than 1 μm in size. The nanoemulsion could
be more easily digested and absorbed by human body, which
could lead to higher bioaccessibility.77,79 In addition, the
nanoemulsion also has much better stability against floccula-
tion and coalescence compared to conventional emulsion.76
The oil phase core may be comprised of oil and one or more
non-polar lipophilic active ingredients, including phytosterols,
curcumin, vitamins, carotenoids, and fucoxanthin. The water
phase shell surrounding the core may also be comprised of
one or more polar or amphiphilic materials, including pro-
teins and polysaccharides.33 When the nanoemulsion droplets
reach their target locations, the lipophilic nutrients could only
be released from the droplets after the oil phase has been
digested and they could then be incorporated into mixed
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Fig. 4 Types of nanostructured delivery systems applied in fucoxanthin encapsulation. The green triangle represents fucoxanthin, which is actually
yellow-brown (adapt with permission from Wei et al., 201979 and Katouzian89).
micelles to exert their effects.77 The release rate of the encapsu-
lated components in these systems depends on the rate of
enzyme digestibility of the nanoemulsion droplets.
Nanoemulsion droplets have a much higher oil–water inter-
facial surface area than that of conventional emulsions, and
therefore they could be digested more rapidly.76
Ma et al. (2019)33 formulated fucoxanthin-loaded oil-in-
water nanoemulsion by using medium-chain triacylglycerol oil
as the surfactant, sodium azide as the anti-microbial agent,
and dissolving emulsifiers (whey protein isolate, modified
lecithin, and gum arabic) in water as the continuous phases.
The oil-in-water (O/W) nanoemulsion was produced via high
pressure homogenization technique at ambient temperature,
in which the ratio of the continuous phase to the dispersed
phase is 9 : 1. The obtained emulsion droplets ranged from
136 nm (whey protein isolate), 140 nm (modified lecithin), to
897 nm (gum arabic), and had improved stability and bioacces-
sibility for the loaded fucoxanthin. It was discovered that the
type and concentration of the emulsifier used significantly
influenced the stability and bioaccessibility of the entrapped
fucoxanthin. The release of fucoxanthin from these systems
was studied in an in vitro digestion model; the release rate was
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shown to decrease in the order of whey protein isolate > modi-
fied lecithin > gum arabic, with bioaccessibility indexes of
92.5%, 44.6%, and 36.8%, respectively. In order to improve the
chemical stability of fucoxanthin during storage, modified
lecithin, whey protein isolate, and Tween 20 were used as
emulsifiers for the preparation of fucoxanthin-loaded O/W
emulsion by using the microchannel emulsification (MCE)
method.93 The sketch diagram in Fig. 5A showed the gene-
ration of droplets through MCE. According to the results,
monosized droplets (Fig. 5B) were successfully generated and
evenly distributed on the microchannel array plates (MCs),
and closely-packed droplets (Fig. 5C) were observed under a
microscope. This emulsion-based delivery system could signifi-
cantly improve the chemical stability (Fig. 5D and E) of fucox-
anthin, and performed well for the slow release of fucoxanthin
and free fatty acid (Fig. 5F). In vitro digestion showed that the
bioaccessibility of fucoxanthin could be enhanced by these
emulsion-based delivery systems.93 Both the liquid state and
powder form of fucoxanthin-loaded nanoemulsion could be
used to improve the shelf life and nutritional value of func-
tional foods with their increased bioaccessibility for
fucoxanthin.33
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Fig. 5 The formation, structure, and morphology of the o/w emulsions and the performance of the encapsulated fucoxanthin (FX): sketch diagram
used for the generation of droplets from microchannel array plates (A). Photographs of droplet generation (B) and the closely-packed droplets (C)
under the microscope. Storage stability photos (D), chemical stability (E), and the FFAs released (F) of monodisperse O/W emulsions encapsulating
FX under different temperatures and times. WPI: Whey protein isolates, ML: modified lecithin HPH: high pressure homogenization, FFAs: free fatty
acids (reproduced with permission from Ma et al., 2020;93 refer to this text for more details).

Molecular nanocomplexes. Molecular nanocomplexes here
refer to the autonomous assembly of host molecules (biopoly-
mers such as proteins and polysaccharides) and ligand mole-
cules (functional active ingredients) bound together by non-
covalent interactions between them.4,32 Zhu et al. (2017)32
assembled nanocomplexes consisting of fucoxanthin and whey
proteins. Spectroscopic and molecular docking analyses
showed that the van der Waals force, hydrogen bonding, and
hydrophobic interaction were the major driving forces for the
formation of whey protein–fucoxanthin nanocomplexes. In the
presence of fucoxanthin, the skeleton structures of whey pro-
teins (including BSA, β-Lg, and α-La) were opened, and then
nanoscale protein aggregates with fucoxanthin molecules were
formed. Zhu et al. (2019)78 also constructed a different type of
nanocomplexes using whey protein isolate through its ligand-
binding and complex coacervation property with fucoxanthin
and lysozyme, respectively. FT-IR spectroscopy and molecular
docking analyses revealed that fucoxanthin was successfully
encapsulated into the heteroprotein complex coacervates, and
the heteroprotein complexes exhibited a higher loading
efficiency compared to the single-protein complexes (82.36%
of whey protein isolate-fucoxanthin-lysozyme, while 55.60% of
whey protein isolate-fucoxanthin) and better protection for
fucoxanthin against heating, long-term storage, and simulated
gastrointestinal environments. Liu et al. (2019)4 produced
fucoxanthin-loaded nanocomplexes composed by oleic acid

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Food & Function
and bovine serum albumin (BSA) that were stabilized via the
ligand-binding property of BSA with fucoxanthin and oleic
acid. When the molar ratio of fucoxanthin, oleic acid, and BSA
was 5 : 4 : 1, the obtained complexes (size ∼265 nm) with good
transparency (transmittance nearly 90%) were acquired.
Besides, the nanocomplexes with oleic acid as the protein co-
ligand exhibited 5 times higher loading efficiency than that of
the ones with no oleic acid, and the anti-oxidative capability of
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fucoxanthin in mice eyes was improved by 71.02%.
Biopolymer nanoparticles. Biopolymer nanoparticles used
for the delivery of hydrophobic bioactive ingredients in food,
pharmaceutical and cosmetic industries are typically smaller
than 1 μm in size.71,76 Typically, fucoxanthin-loaded bio-
polymer nanoparticles consist of hydrophobic cores and
hydrophilic shells.5,30 Hydrophobic proteins (whey protein,
casein, zein, etc.) firstly assemble to form the spherical inner
core and hydrophilic polysaccharides ( pectin, carrageenan,
chitosan, etc.) can then be coated on the core surface to form
the outer shell.5,70,71 Fucoxanthin can be embedded in the
protein core primarily via hydrophobic interactions and
soluble polysaccharides were adsorbed on the surface of
protein core mainly through electrostatic interactions in order
to improve the stability, water dispersibility, and bioaccessibil-
ity of the entire nanoparticle system.6,30 The design of an
appropriate shell structure in biopolymer nanoparticles is very
conducive for the stability and efficient delivery of bioactive
components. For example, the use of alginate or chitosan
instead of pectin to form the shell layer of the nanoparticles
can significantly improve the stability of zein or casein-based
core–shell nanoparticles, which could be advantageous to
improve the water dispersion and slow-release of bioactive
components.5,94 Natural biopolymers are preferred as raw
materials to prepare core–shell nanoparticles for the nano-
encapsulation of hydrophobic bioactive components includ-
ing fucoxanthin to improve their water solubility and
bioaccessibility.69–71 Koo et al. (2016)5 used casein/chitosan
core–shell nanoparticles for encapsulating fucoxanthin and
their morphology, structure, encapsulation efficiency, water
dispersibility, and bioavailability were investigated.
According to their results, the fucoxanthin-loaded core–shell
nanoparticles with a smooth spherical surface were
∼277 nm in size with an encapsulation efficiency over 71%
and a polydispersity index less than 0.40 in water. The
bioaccessibility (simulated digestion in vitro) of fucoxanthin
from the core–shell nanoparticles (36–61%) was higher than
that of free fucoxanthin (26–48%). The pharmacokinetic
study indicated that the bioavailability (280 nmol h L−1 to
531 nmol h L−1) and mucin adsorption level (34.7% to
61.2%) of fucoxanthin from the core–shell nanoparticles
were greatly enhanced. In addition, the existence of calcium
ions in the core–shell nanoparticles helps to create a more
compact protective structure, thus reducing the degradation
and destruction of fucoxanthin by light, oxygen, heat, and
gastric acid. The obtained fucoxanthin-embedded core–shell
nanoparticles can be used in functional beverages including
milk.65,66
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4.3. Processing techniques for nano/micro-encapsulation
Processing techniques to prepare nano/micro-encapsulation
systems developed nutraceuticals have been gradually applied
for the preparation of functional nanoencapsulated
fucoxanthin.31–33,78,95 Several common nano/micro-encapsula-
tion methods for fucoxanthin are summarized in Table 3.
Generally speaking, nano/micro-encapsulation techniques
could be categorized into several classes: physical mixing,
chemical cross-linking, enzymatic conjugation, and physico-
chemical gelation. Physical mixing methods for nano/micro-
encapsulation include freeze drying, high pressure homogeniz-
ation, microchannel emulsification, and sonication.75,93
Chemical cross-linking techniques include anti-solvent pre-
cipitation, solvent evaporation, ion crosslinking, and
polymerization.5,69,71,96 Enzymatic conjugation technique
involves the generation of nano/micro-encapsulation via
enzyme-aided mechanisms, which is different from Maillard
reaction that is another reaction that can form protein-polysac-
charide conjugates.97–99 In physicochemical methods, nano/
micro-encapsulation is generated via complex coacervation
and ionic gelation through synergistic physical and chemical
procedures.75,80 Hereafter, advances in some specific nano/
micro-encapsulation techniques are discussed in more detail.
Physical methods. Among all the physical methods, freeze-
drying is the one most widely used in pharmaceutical and
functional food industries, especially for the preparation of
thermally sensitive loading liposomes with small particle size
(within 200 nm) and good stability, which could be con-
veniently sterilized and stored.85 With the freeze-drying
method, hydrophobic fucoxanthin can be easily entrapped in
liposomes and its bioactivity could also be fully utilized. Koo
et al. (2016)5 developed procedures to prepare fucoxanthin-
loaded casein–chitosan composite nanoparticles by the freeze-
drying method. In their approach, casein (CN) was completely
hydrated and mixed with fucoxanthin-enriched fraction (FX-fr)
of ethanol solution. Crosslinking between FX and CN was
induced by calcium ions, and the FX–CN complexes were pre-
pared by electrospray method. Chitosan was coated onto the
surface of the complexes and the fucoxanthin-loaded casein–
chitosan composite nanoparticles (FX-CS–CN) were obtained
after freeze-drying at −120 °C for 48 h. Fig. 6 shows the freeze-
drying process and the resultant nanoencapsulated fucox-
anthin. After storage at 26 °C for 4 weeks, the free FX in water
was degraded to about 30% of the initial amount, while more
than 80% of FX in the two nanoparticles were retained under
the same conditions. Koo et al. (2016)5 suggested that FX-CS–
CN nanoparticles obtained by freeze-drying showed enhanced
bioaccessibility (26%–61%), bioavailability (280 nmol h/L–
531 nmol h L−1) and water dispersibility compared to that of
free fucoxanthin and binary FX–CN particles, which could be
more suitable for food industry. As an alternative physical
mixing method, Ma et al. (2019)33 constructed a novel fucox-
anthin-loaded oil-in-water emulsion by using high-pressure
homogenization at 100 MPa with 4 passes. In brief, due to the
special purpose of encapsulation, a variety of physical techno-
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Table 3 Common nano/micro-encapsulation techniques for fucoxanthin

Classes Techniques Advantages Disadvantages

Physical mixing Freeze drying - Maintains the natural properties of the - Limitation in types of coating material
method material to the greatest extent and minimize its
loss; especially suitable for handling heat
sensitive materials.
- Suitable for encapsulating many types of - Loss of compound bioactivity during freezing
compounds process
- The operation is simple. - High operational cost
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- The rehydration of the material is easy.

- Easily adaptable at larger scales
High pressure - The pressure applied to the material is - Energy consumption and the equipment is
homogenization uniform. vulnerable to damage
- The particle size is small and uniform. - Limitation in types of coating material and
the viscosity cannot be too high
- Less heat, thus basically keep the material
properties unchanged.
- Is able to ration the material
Sonication - Saves time - The temperature rises sharply during the
treatment.
- Minimizes sample loss - Materials are susceptible to inactivation.
- Is able to process lots of samples
- Simple technique
Emulsification - High reproducibility - Not suitable for volatile compounds and high
affinity molecules for continuous phase
- High loading efficiency - The active compound might be lost during
- Easier to industrialize due to simple and solvent evaporation.
flexible steps
Chemical Anti-solvent - Simple preparation process The organic solvents involved may make the
crosslinking method precipitation - The preparation conditions are easy to control. whole encapsulation system contaminated with
- Short synthesis period odor and its removal is more troublesome.
- Has a low cost
Ion crosslinking - Easy approach - Only certain compounds can be
encapsulated.
- Controlled release of encapsulated compounds - Positively charged coating material might
- Longer period of encapsulation cause a change in the electron donating affinity
of the encapsulated bioactive compound.
Enzymatic Enzymatic - Strong combination, good stability - Limitation in the types of coating material
conjugation method conjugation and usuallys occur between proteins and
reducing sugars
- Safe, efficient and pollution-free - Only certain enzymes work
- Simple operation and low cost
Physicochemical Coacervation - High value active substances can be - Depends on the electrostatic interaction of
method encapsulated, especially unstable compounds. the compounds with the coating material
- Low production cost for simple coacervation - Only few selected compounds can be
encapsulated
- High loading efficiency - High production cost for complex
coacervation
Ionic gelation - It facilitates easy reaction and the temperature - Raw materials are expensive and may involve
is low. organic solvents.
- The mixture is uniform at the molecular level. - The gelation process takes a long time, days
or weeks.
- Various new materials can be prepared by - There are a large number of pores in the gel
selecting suitable conditions. due to gas and organic material escaping.
Shrinkage may occur during drying.

logies and methods with different characteristics can be
selected to precisely process the delivery system of the bio-
active compound.
Chemical methods. At present, several research studies are
focused on the anti-solvent precipitation method to construct
natural biopolymer-based delivery systems for the application
of bioactive compounds in functional foods.30,69,94 Since the
high-energy emulsifying devices, such as high-pressure hom-
ogenizer, were widely used to manufacture the stable and
uniform emulsions in pharmaceuticals and cosmetics, were
relatively expensive for the food industry. Li et al. (2018)30 suc-
cessfully fabricated fucoxanthin-loaded zein/caseinate compo-
site nanoparticles by using such a facile anti-solvent precipi-
tation method at neutral pH. These conditions are easy to be
controlled, the synthesis cycle is short, and the material cost is
low. However, the stability, bioaccessibility, anti-oxidative
activity, and anti-proliferative activity of encapsulated fucox-
anthin were appreciably higher compared to the free ones.
However, such a simple preparation process may involve the
use of organic solvents, which are troublesome to remove and

Food Funct. This journal is © The Royal Society of Chemistry 2020


Food & Function
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Fig. 6 Study of fucoxanthin-loaded casein–chitosan nanoparticles using the freeze-drying process. FX: Fucoxanthin, CN: casein, CS: chitosan,
FXOH: fucoxanthinol (reproduced with permission from Koo et al., 2016;5 refer to this text for more details).
easily pollute the environment. Another chemical method that
also involves the use of organic solvents is the solvent
exchange method. Oliyaei et al. (2020)34 developed a nano-
carrier based on porous starch and halloysite nanotube by
using the methods of solvent exchange and vacuum hybrid for
improving the stability and sustained release of fucoxanthin.
The outcome of this nanocarrier suggested that the modified
starch prepared by the solvent exchange method has a
uniform and dense porous structure. This structure can sig-
nificantly increase the encapsulation efficiency, loading
capacity, stability and slow-release of fucoxanthin after it is
mixed with halloysite nanotube in vacuum.
Enzymatic conjugation and maillard reactions. Enzymatic
conjugation is noted for its strong specificity and mild reaction
conditions. Also, it is a kind of covalently cross-linking tech-
nique to create protein–polysaccharide conjugated particles for
encapsulation, especially in the presence of oxidases or
TGase.100,101 The working mechanism of the two types of
enzymes is that TGase catalyzes simple acyl transfer reactions
between glutamine residues and free amino groups, while oxi-
dases (including laccase and tyrosinase) catalyze oxidation
reactions between highly reactive quinone residues of the oxi-
dized proteins and nucleophilic substituents of polysacchar-
ides.97 The green fluorescent protein–chitosan conjugated par-
ticles for encapsulation, produced by such a enzymatic conju-
gation method, were observed to have the smart attribute of
pH-responsiveness, which will provide the possibility for the
stable delivery and even the targeted controlled release of the
encapsulated fucoxanthin in the treatment of hypoxic
This journal is © The Royal Society of Chemistry 2020
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cancer.101,102 In addition, protein–polysaccharide conjugated
particles for encapsulation could also be obtained by another
covalent crosslinking reaction, namely, the Maillard reaction,
which does not require enzymes. Wang et al. (2016)98 produced
special O/W emulsions with the cross-linked interfacial film of
BSA–dextran conjugated particles for encapsulation. Also, such
a BSA–dextran conjugated particle, as the emulsifier and the
stabilizer of the O/W emulsions, was formed by the Maillard
reaction during the heat treatment. The improvement of oral
bioavailability in mice suggested that this kind of emulsion
system produced by Maillard reaction is a good oral delivery
system for hydrophobic compounds (fucoxanthin may also be
included).
Physicochemical methods. Complex coacervation is one of
the most convenient techniques in physicochemical methods
to encapsulate high value active substances to prevent their
molecular degradation and oxidation, especially for unstable
bioactive compounds, such as essential oils, polyphenols, and
carotenoids.103,104 The formation of complex coacervates
usually occurs between two biomacromolecules with opposite
charges, such as proteins or polysaccharides, which can be
used for the stable nano/micro-encapsulation of hydrophobic
bioactive compounds.103,105 By combining all the advantages
of two or more different wall materials, the obtained coacer-
vates may have new functional properties. The nano/micro-
encapsulation system constructed by complex coacervation
technology has a high loading capacity but its stability
depends on the electrostatic interaction of the embedded com-
pound with the coating material.103 Also, only few selected
Food Funct.

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compounds can be encapsulated by such a technology with a
high production cost. As mentioned above, a fucoxanthin
vector based on the complex coacervation of whey protein iso-
lates and lysozyme was successfully constructed.78 The process
for preparing molecular nanocomplexes through heteroprotein
complex coacervation was easy to carry out but the obtained
encapsulation system exhibited excellent loading efficiency
and provided remarkable protection by fucoxanthin against
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heat, light, and simulated gastrointestinal environments.
Another physicochemical method frequently used is ionic gela-
tion technology, and various delivery systems can be prepared
by selecting suitable coating materials and conditions. In this
respect, the chitosan-sodium tripolyphosphate-glycolipid
nanogel was successfully prepared by ionic interactions
between two oppositely charged materials in order to improve
the stability and bioavailability of fucoxanthin with highly
efficacy.31 In addition, Zhu et al. (2019)72 reported that the
polymerization between whey protein and fucoxanthin endow
the nanocomplexes system with good delivery ability through
simple self-assembly, which is demonstrated by its physical
stability, encapsulation efficiency, and bioaccessibility.
5. Food or nutraceutical applications
Adding the encapsulated fucoxanthin into foods and nutraceu-
ticals as a functional component can offer special nutritional
value to the product, cover, or preserve the flavor as well as
reduce the degradation or loss of fucoxanthin, which provides
many advantages for food processing. The effective encapsula-
tion of fucoxanthin based on casein and whey protein in milk
has been reported. Mok et al. (2016, 2018)65,66 incorporated
fucoxanthin extracted from brown algae into skimmed and full
fat milk by using spray drying methods, which not only
improved the flavor, nutritional, and functional value of ordin-
ary milk but also enhanced its stability and bioavailability due
to the ligand binding characteristics between milk protein and
fucoxanthin during the encapsulation. Koduvayur
Habeebullah, Surendraraj, & Jacobsen (2018)106 encapsulated
fucoxanthin in fish oil, which can be either formulated into
fucoxanthin-loaded oil in the water emulsion for functional
foods or directly processed into fucoxanthin-loaded fish oil
soft capsules. Encapsulated fucoxanthin in fish oil is also
Table 4 Fucoxanthin products in food-nutraceutical applications
Products Encapsulation system
Concentrated extracts of fucoxanthin Unencapsulated
Microencapsulated fucoxanthin powder β-Cyclodextrin
microcapsule
A water soluble fucoxanthin dry powder O/W emulsion system
Fucoxanthin fish oil soft capsule O/W emulsion system
Full fat and skimmed milk powder containing Molecular nanocomplexes
fucoxanthin
Food Funct.
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Food & Function
helpful to improve the cardiovascular and cerebrovascular dis-
eases, and it has the effects of lowering the blood pressure as
well as reducing blood lipid, anti-oxidation, and ocular
protection.106,107 Similarly, Saravana et al. (2019)108 success-
fully developed a κ-carrageenan-based nano-emulsion, which
can be used to encapsulate fucoxanthin-rich seaweed oil
through ultrasound-assisted emulsification in functional
foods, beverage systems, and pharmaceuticals.
The research on fucoxanthin is at the stage of stable embed-
ding and delivery. Owing to the lack of rigorous in vivo metab-
olism research and clinical trials, the practical application of
fucoxanthin in food and nutraceutical is still scarce (Table 4),
which leads to few fucoxanthin embedded foods and nutraceu-
ticals in the market. However, with the development of science
and technology and the deepening of related research, there
will be a boom in the development of fucoxanthin-fortified
foods and nutraceuticals in the next few years.
6. Challenges and future trends
It is still a challenge to incorporate fucoxanthin into food or a
nutrient supplement due to its poor stability, low solubility,
and weak bioaccessibility. Although nano/micro-encapsulation
of fucoxanthin could be utilized to effectively improve its stabi-
lity, as shown by in vitro investigations,5,31,33,58 major draw-
backs still exist: the nanoemulsion requires more complex pro-
cesses and surfactants than conventional emulsions, which
may increase the costs and potential toxicity; there may be
more regulatory concerns for nanoemulsions than convention-
al emulsions. Furthermore, the low loading capacity of the
current approaches could limit the amount of fucoxanthin
reaching the targeted sites efficiently in vivo. Reducing the use
of surfactants or exploring some natural surfactants should be
considered when developing nano/micro-encapsulation
systems. The improvement and optimization of coating
materials, structural modification, and/or the introduction of
new carrier materials are still needed for nano/micro-encapsu-
lation delivery systems of fucoxanthin to increase the targeting
and loading performance. Research in the relevant fields need
to move beyond the stages of construction, characterization,
and in vitro simulated digestion to focus more on the related
pharmacokinetics, metabolomics, and even clinical studies to
Patent number Technical fields
CN201110155266. Natural products’ separation and
X extraction
CN201410490630.1 Natural products’ application
CN201510407570.7 Natural products’ application
CN201610698526.0 Health products and
nutraceutical
applications
Not found Food processing
This journal is © The Royal Society of Chemistry 2020

Food & Function
examine their practical tumor intervention performance
in vivo. At the same time, the work on safety and reliability is
also quite lacking.
In the future, the pharmaceutical industry will benefit the
most from the nano/micro-encapsulation technology of fucox-
anthin, which makes it possible for the full therapeutic poten-
tial of fucoxanthin to be realized against chronic diseases such
as cancer.36 Tumor patients often suffer from poor appetite
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and reduced digestive effectiveness due to the side effects pro-
duced by chemotherapy. They are more likely to suffer from
malnutrition than normal healthy people. Therefore, a variety
of natural functional ingredients including fucoxanthin
should be considered as nutritional supplements for tumor
patients. Functional foods that can satisfy both the gastro-
nomic and dietary protective needs of tumor patients could be
developed for the benefit of tumor patients. Certainly, for such
foods, sensory characteristics, such as flavor, texture, and
taste, along with the nutritional/dietary needs, should all be
considered for their proper design and production.109 In
addition, nano/micro-carriers with unique functionality,
including magnetic responsiveness and pH responsiveness,
can be used for the targeted delivery of fucoxanthin to maxi-
mize its tumor intervention efficacy. Magnetic nanoparticles
have been explored as tumor drug carriers due to their high
specific surface area, favorable biocompatibility, low toxicity,
and strong magnetic responsiveness.110 Also, they are usually
composed of magnetic cores with polymer coating over the
surfaces so as to reduce the agglomeration of nanoparticles
and to improve the affinity of the delivery system towards tar-
geted organs.111 Furthermore, such magnetic nanoparticles
can generate heat in an external alternating magnetic field and
by moving the magnetic field position, they can be artificially
controlled to produce hyperthermia at specific focal sites and
kill the tumors.112 With the rapid growth of solid tumor, the
hypoxia caused by the imbalance of oxygen supply and con-
sumption tends to cause systemic or local acidulated environ-
ment.102 In this respect, a delivery system with pH responsive-
ness, which may be produced by green fluorescent protein–
chitosan conjugate, is critically important for the stable deliv-
ery and targeted controlled release of fucoxanthin in the treat-
ment of hypoxic tumor.101 In the future, the nano/micro-
encapsulation technology of fucoxanthin will inevitably focus
on its application in targeted controlled release, which is of
great significance for the development of fucoxanthin-based
tumor intervention products.
7. Conclusion
Fucoxanthin is a natural carotenoid abundant in marine
brown algae with a huge potential of tumor intervention
efficacy. The direct addition of fucoxanthin and its derivatives
into foods and nutraceuticals is neither easy nor effective due
to their low solubility, stability, and bioaccessibility. Nano/
micro-encapsulation offers a possible solution to this problem.
By this technique, fucoxanthin could be introduced into func-
This journal is © The Royal Society of Chemistry 2020
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Review
tional foods, nutraceuticals, or nutrient supplement products
for the prevention and management of tumor. This article pro-
vides a comprehensive review on the latest progress of nano/
micro-encapsulation methods in enhancing the bioaccessibil-
ity of fucoxanthin especially with the aim of fully realizing its
tumor intervention efficacy. Natural edible materials such as
whey protein, casein, zein, gelatin, and starch could be used to
fabricate lipid-based, gel-based, or emulsion-based nano/
micro-delivery systems for fucoxanthin. Based on the pub-
lished literature, it seems that the nano/micro-delivery system
with whey protein as the encapsulation material seems to be
more conducive for the stable encapsulation and safe delivery
of fucoxanthin. To make nano/micro-capsules, various
advanced processing techniques can be utilized, each with their
own advantages and disadvantages, e.g., freeze-drying, high
pressure homogenization, sonication, anti-solvent precipitation,
coacervation, ion crosslinking, ionic gelation, emulsification,
and enzymatic conjugation. Past researches have indicated that
nano/micro-capsules formulated using either coacervation (best
performance in terms of fucoxanthin loading) or freeze-drying
(best performance in terms of retaining fucoxanthin activity)
were among the most effective in stabilizing and enhancing the
bioaccessibility of fucoxanthin. It is conceivable that the explora-
tion and utilization of encapsulated fucoxanthin will continue
in the coming years to bring more health benefits to functional
foods, nutraceuticals, and nutrient supplements. For the poten-
tial of fucoxanthin to be fully realized, further studies on the
metabolomics of fucoxanthin and its derivatives in vivo, the con-
tinued improvement of performance of nano/micro-encapsula-
tion techniques, and the investigation into new synergistic
nanocarriers are all needed. The information presented in this
paper could be utilized by a broad community of multidisciplin-
ary researchers from foods, clinical, materials, and colloid
sciences working at the interface of chemistry and biology to
keep the march towards taking full advantage of fucoxanthin to
improve human health.
Author contributions
Hang Qi and Xing Chen: Conceptualization, methodology,
software. Chunyan Wang: Resources, investigation, writing,
original draft preparation. Yoshimasa Nakamura:
Visualization, validation, reviewing. Chenxu Yu: Reviewing and
editing. All the authors read, edited, and approved the final
manuscript.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was financially supported by The National Key
Research and Development Program of China
Food Funct.

Review
(2019YFD0902001), Young Top Talents Project of Liaoning
Revitalization Talents Program (XLYC1807166), and Dalian
Science and Technology Foundation for Distinguished Young
Scholars (2018RL07).
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