foods

Review
Valorisation of Micro/Nanoencapsulated Bioactive
Compounds from Plant Sources for Food Applications
Towards Sustainability
Valter F. R. Martins, Manuela E. Pintado, Rui M. S. C. Morais and Alcina M. M. B. Morais *

CBQF—Centro de Biotecnologia e Química Fina—Laboratório Associado, Escola Superior de Biotecnologia,

Universidade Católica Portuguesa, Rua Diogo Botelho, 1327, 4169-005 Porto, Portugal
* Correspondence: [email protected]

Abstract: The micro- and nanoencapsulation of bioactive compounds has resulted in a large im-
provement in the food, nutraceutical, pharmaceutical, and agriculture industries. These technologies
serve, on one side, to protect, among others, vitamins, minerals, essential fatty acids, polyphenols,
flavours, antimicrobials, colorants, and antioxidants, and, on the other hand, to control the release
and assure the delivery of the bioactive compounds, targeting them to specific cells, tissues, or organs
in the human body by improving their absorption/penetration through the gastrointestinal tract. The
food industry has been applying nanotechnology in several ways to improve food texture, flavour,
taste, nutrient bioavailability, and shelf life using nanostructures. The use of micro- and nanocap-
sules in food is an actual trend used mainly in the cereal, bakery, dairy, and beverage industries, as
well as packaging and coating. The elaboration of bio capsules with high-value compounds from
agro-industrial by-products is sustainable for the natural ecosystem and economically interesting
from a circular economy perspective. This critical review presents the principal methodologies for
performing micro- and nanoencapsulation, classifies them (top-down and/or bottom-up), and dis-
cusses the differences and advantages among them; the principal types of encapsulation systems; the
natural plant sources, including agro-industrial by-products, of bioactive compounds with interest
Citation: Martins, V.F.R.; Pintado,
for the food industry to be encapsulated; the bioavailability of encapsulates; and the main techniques
M.E.; Morais, R.M.S.C.; Morais,
A.M.M.B. Valorisation of Micro
used to analyse micro- and nanocapsules. Research work on the use of encapsulated bioactive
/Nanoencapsulated Bioactive compounds, such as lycopene, hydroxytyrosol, and resveratrol, from agro-industrial by-products
Compounds from Plant Sources for must be further reinforced, and it plays an important role, as it presents a high potential for the
Food Applications Towards use of their antioxidant and/or antimicrobial activities in food applications and, therefore, in the
Sustainability. Foods 2023, 12, 32. food industry. The incorporation of these bioactive compounds in food is a challenge and must be
https://doi.org/10.3390/ evaluated, not only for their nutritional aspect, but also for the chemical safety of the ingredients.
foods12010032 The potential use of these products is an available economical alternative towards a circular economy
Academic Editors: Dimitrios and, as a consequence, sustainability.
Arapoglou and Giorgos Markou
Keywords: microencapsulation; nanoencapsulation; encapsulation techniques; bioactive compounds;
Received: 4 December 2022
plant; agro-industrial by-products; bioavailability; food applications; sustainability
Revised: 12 December 2022
Accepted: 15 December 2022
Published: 22 December 2022

1. Introduction
In recent years, awareness has led to healthy options when buying food, and con-
Copyright: © 2022 by the authors. sumers, in general, prefer foods that do not only satisfy their primary needs, but that
Licensee MDPI, Basel, Switzerland. also include health effect promoters besides the nutrients, and that can replace synthetic
This article is an open access article additives by natural bioactive compounds, which may prevent illnesses. However, natural
distributed under the terms and
bioactive compounds, although safe, sometimes present an unpleasant taste or odour
conditions of the Creative Commons
and instability. The direct incorporation of these compounds in food is often difficult,
Attribution (CC BY) license (https://
so nanoencapsulation constitutes an alternative to solve this issue. The use of nano- or
creativecommons.org/licenses/by/
microcapsules in food is a trend used in the cereal, bakery, dairy, and beverage industries,
4.0/).

Foods 2023, 12, 32. https://doi.org/10.3390/foods12010032 https://www.mdpi.com/journal/foods

Foods 2023, 12, 32 2 of 23

as well as packaging and coating [1]. Encapsulated compounds in foods include vitamins,
essential fatty acids, minerals, flavours, antimicrobial agents, colorants, antioxidants, and
polyphenols [2]. The incorporation of nutraceuticals [3] in food presents an issue, as both
the nutritional purpose and the chemical safety of ingredients must be considered and
evaluated [1].
The nanoencapsulation of bioactive compounds has brought large improvements to
the food, nutraceutical, pharmaceutical, and agriculture industries. This technology allows
the protection of bioactive compounds applied to different matrices and the control of their
release. The elaboration of bio capsules with natural bioactive compounds is a challenge
nowadays. The use of bioactive compounds extracted from by-products is economically
interesting in the scope of a circular economy approach, and is more sustainable for the
natural ecosystem [4,5].
Nanoencapsulation serves at the same time to target cells, tissues, or organs and to
control the release and delivery of bioactive molecules. It also serves to protect the bioactive
compound from several reactions that can modify the molecule or alter its bioactivity.
Factors such as temperature, acidity, hydrolysis, and oxidation due to light exposure are
some of the hazards for bioactivity. The advantages of this technology include (i) allowing
targeting all the bioactive beneficial characteristics of the compounds to specific targets,
(ii) controlling the release of the bioactive components, (iii) allowing the concentration of
the compound to be decreased, thus preserving it in hostile mediums and maintaining its
natural characteristics, (iv) preventing interactions between the bioactive molecules and
other food ingredients, and (v) presenting a high solubility and dispersibility [1].
Nanoencapsulation deals with several types of materials on the atomic, molecular, and
supramolecular scale, normally from 1 to 100 nm; nevertheless, some nanocapsules may
present sizes up to 600 nm [6]. Nano refers to the size of 10−9 m, and the British standard-
ization body defines nanotechnology as the conceptualisation, elaboration, characterization,
and application of the products (nanocapsules) and systems [7].
In the last years, the food industry has applied nanotechnology in diverse forms to
improve food texture, flavour, taste, consistency, nutrient bioavailability, and shelf life
using nanostructures in stable emulsions. In addition, nanotechnology also presents well-
known benefits in the fields of nutraceuticals, food microbiology, and nutrient delivery,
by improving nutrient absorption in the gastrointestinal tract [8]. In food packaging,
nanoencapsulation has improved materials by enhancing their mechanical strength and by
producing antimicrobial films and nanosensors to detect pathogens or specific compounds,
e.g., indicators of disease conditions, which are important tools to enlighten consumers
about food safety issues [9].
Actually, not only value-added components of foods are in focus. It is also possible to
remove undesirable components from modified functional foods, such as sugars, salt, and
fats to obtain more healthy products.
It is important to distinguish microencapsulation from nanoencapsulation, with the
principal difference being the size, but with the two also having different functions. The
dimensions that distinguish microparticles from nanoparticles is still under debate. In
microencapsulation, the scale varies between 1 and 8000 µm (Table 1). Other authors, such
as Rossi et al. [5], have stated that nanocapsules and microcapsules are 10–1000 nm and
3–800 µm in diameter, respectively. Shishir et al. [10] have claimed that microcapsules stay
in the range of 1 to 1000 µm, sub-microcapsules range from several hundred nanometres to
less than 1 µm, and nanocapsules range from one to several hundred nanometres. Some
authors have proposed a diameter inferior or equal to 100 nm for nanoparticles [11] and
the range for colloid associations as 5 to 100 nm to be considered a nanoparticle [12]. The
functionalities of microencapsulation are (i) the protection of bioactive compounds; (ii) the
control of the release profile; (iii) the masking of undesirable flavours; (iv) the improvement
of flow properties; (v) an increase in the shelf life; and (vi) product enrichment with
specific nutrients. Very similarly, the functions of nanoencapsulation are (i) to reduce the
practical size and create a restricted distribution of particles; (ii) to increase the surface
Foods 2023, 12, 32 3 of 23

area; (iii) to improve the delivery of bioactive molecules; (iv) to increase the bioavailability
of encapsulated compounds; (v) to increase the physical stability and extend the shelf
life; (vi) to increase precision targeting and to promote passage through fenestrated cells;
(vii) to strengthen the barrier between bioactive and other compounds; and (viii) to improve
intracellular absorption [10].

Table 1. Micro- and nanoencapsulation methodologies.

Technology Short Description Shell and Core Capsule Size References

Core: curcumin; 320 nm
Absence of heat; accumulation of Shell: zein [8,13]
Electrospinning nanoencapsulated electrospun fibre;
(TD) may form a film. Core: vitamin E;
Shell: chitosan - [14]

Core: essential oils;

Shell: cross-linking agent is 80 nm–900 µm [15]
calcium chloride
Electric field to distort the interface of
Electro-spraying the droplet; high direct voltage - 5 nm–500 nm [8]
(TD) (0–30 kV); frequency, 30 kHz; Core: quercetin;
discharge power, 45 kJ/m2 . 5 nm–100 µm [16]
Shell: polyvinylpyrrolidone K10
Core: vitamin E;
Shell: chitosan - [14]

Core: hemp cannabidiol;

To dissolve bioactive and emulsifier in Shell: low-density lipoprotein 200 nm–5000 µm [8,17,18]
water or oil phase (w/o; o/w or (LDL) with
Emulsification o/w/o; w/o/w); nanoemulsions can carboxymethylcellulose (CMC)
(TD) be obtained using homogenizer, Core: limonene; 50–1000 nm
ultrasonicator, and microfluidizer. Shell: maltodextrin, starch, [7]
543–1292 nm
tween-40
Core: curcumin;
Emulsification of the polymer solution Shell: poly lactide-co-glycolide 45 nm
Emulsification solvent into an aqueous phase and evaporation (PLGA)
evaporation [7]
of the solvent, causing the polymer Core: quercetin;
(TD) precipitation as nanospheres. 130 nm
Shell: polycaprolactone (PLA)
To heat at 125 ◦ C; to pour into a Core: citrus oils;
Extrusion coating
nitrogen-pressurized chamber; to Shell: corn syrup solids and - [19]
(TD)
extrude into a dehydrating liquid. glycerine
Core: vitamins, hormones,
enzymes;
- [17,19]
To disperse lipid molecules in water, Shell: one or more layers of
Liposome entrapment with bioactive agent in lipid or water lipids
(TD) phase; to reduce size by high shear or
extrusion. Core: vitamin C and iron;
Shell: egg phosphatidylcholine, 10–1000 µm [20]
cholesterol, DL-α-tocopherol
Core: polyphenol;
To melt the coating; to disperse the - [21]
Shell: carbohydrate melt
Melt extrusion bioactive in the coating; to incorporate
(TD) the volatile compound in a Core: essential oils, flavours;
thermoplastic matrix and force it Shell: sucrose, corn syrup, gums, 300–5000 µm [22]
through a nozzle. or maltodextrins
Core: polyphenols;
To melt the coating; to disperse the - [21]
Melt injection Shell: carbohydrate melt
bioactive compound in the coating; to
(TD) extrude through a filter; to cool or Core: essential oil; 200–2000 µm [22]
dehydrate. Shell: corn syrup
Spinning disk and
Preparation of core and shell solutions; Core: canola oil;
centrifugal co-extrusion 150–8000 µm [20,23]
co-extrusion through nozzles. Shell: alginate
(TD)
Core: vitamins and minerals; -
To dissolve the bioactive in a lipid Shell: vegetable oils [19]
Spray chilling solution at 32 to 42 ◦ C; atomization
(TD) (1.2 mm), 15 ◦ C ± 2 ◦ C, 5 bar Core: bacteria (Lactobacillus
pressurized air. acidophilus and Bifidobacterium
animalis subsp. Lactis); 60.9–85.9 µm [24]
Shell: vegetable fat
Foods 2023, 12, 32 4 of 23

Table 1. Cont.

Technology Short Description Shell and Core Capsule Size References

Core: flavour oil; -
Shell: gelling protein [8,17,19]
To prepare oil-in-water emulsion with Core: capsaicin;
Coacervation lipophilic bioactive in oil phase; to mix; 100 nm
Shell: glutaraldehyde
(BU) to produce three immiscible phases; to
Core: bovine serum albumin; [7]
cool; to cross-link.
Shell: chitosan and polyanion 200–580 nm
tripolyphosphate
Co-crystallization Sucrose syrup (95–97◦ Brix); above Coat: sucrose;
120 ◦ C. Shell: polyphenols Below 30 µm [20,25]
(BU)
Core: caffeine; 10–400 µm [17,20,26]
Encapsulation by rapid Shell: glyceryl monostearate
expansion of To create a dispersion of bioactive and
supercritical fluid shell material in a supercritical fluid; Core: lutein;
(BU) 13 MPa, 62 ◦ C, 1 h. Shell: hydroxyl propyl methyl 163–219 nm [7]
cellulose phthalate
Core: vitamins;
Particles suspended at controlled Shell: gums, starches, or 50–500 µm [19]
Fluid-bed coating temperature and humidity; high-speed maltodextrins
(BU) air where the coating material is
atomized; coalescence of drops to form - 20–200 µm [17]
a film. - 100 nm to several mm [27]
Core: garlic and onion oils;
In β-cyclodextrin, with hydrophobic - [8,19]
Shell: cyclodextrin
Inclusion complexation centre and hydrophilic outer surface;
(BU) water molecules replaced by less polar Core: docosahexaenoic acid,
molecules; precipitate recovered and usnic acid;
Shell: β-lactoglobulin and low 100 nm [7]
dried; binding by cyclodextrins, 200 ◦ C.
methoxyl pectin, β-cyclodextrin
Core: Zataria multiflora essential
Protonation of amino groups and oil; Below 200 nm [28]
Ionic gelation interaction with negatively charged Shell: chitosan
(BU) pentasodium triphosphate, Core: jujube pulp and seed
establishing inter- and intra-molecular extracts; 130–270 nm [29]
cross-linkages. Shell: chitosan
Also called solvent displacement;
Nano-precipitation precipitation of polymer from solution; Core: β-carotene; 80–100 nm [7,8]
(BU) only polymer-based wall material can Shell: PLA, PLGA
be used.
Core: Origanum vulgare essential
Phase inversion oil;
temperature To use non-ionic surfactant that Shell: PEG-40 hydroxylated 20–200 nm
changes its solubility with temperature. [30]
(BU) castor oil, polyoxyethylene
4-lauryl ether
Magnetically stirred slowly at room
temperature overnight; heated at 90 ◦ C Core: vitamin C;
Self-assembly technique
for 20 min; dialyzed and lyophilized; Shell: bovine serum albumin and Below 100 nm [31]
(BU) citrus peel pectin
5 mg nanocapsule/mL to obtain the
nanohydrogel.
Lecithin and cholesterol in ethanol
Thin-film hydration dried in vacuum; dried lipidic films Core: vitamin A palmitate;
sonication 76–115 nm [32]
(BU) hydrated with aqueous solution; Shell: lecithin and cholesterol
probe sonication, 1 min.

Freeze drying Oil-in-water emulsion stirred for Core: fish oil;

30 min, 500 rpm; sonicated, 24 kHz, for Shell: whey protein and arabic 1.20–2.08 nm [33]
(TD and BU) 120 s; dried. gum
Core: flavours and edible oils,
orange oil; - [19]
Shell: arabic gum
Core: lutein, catechin;
Shell: maltodextrin,
hydroxylpropyl methyl cellulose 80–219 nm [7]
phthalate
Spray drying To disperse or dissolve the bioactive
(TD and BU) in aqueous coating solution; Core: bacitracin; 3.1–6.6 µm
drying at 300–400 ◦ C. Shell: maltodextrin
[34]
Core: salbutamol sulphate;
0.5–3 µm
Shell: lactose
Core: blackberry aqueous extract;
Shell: arabic gum and - [35]
polydextrose
Foods 2023, 12, 32 5 of 23

Table 1. Cont.

Technology Short Description Shell and Core Capsule Size References

Core: Pelargonium graveolens L.
Ultrasonication To use probe-type sonicator, 50 Hz, for essential oil; 42.6 nm [36]
(TD and BU) 20 min. Shell: chitosan
Storage of the emulsion-loaded yeast Core: chlorogenic acid;
5–10 µm [37]
Yeast encapsulation for the permeation (60 ◦ C) of the Shell: yeast cell
(TD and BU) flavours into the yeast; subsequent Core: limonene;
drying to seal the flavour-filled yeast. 2 µm [38]
Shell: yeast cell
TD—top-down approach; BU—bottom-up approach.

This review aims to perform a critical analysis of (i) the different methodologies to
carry out micro- and nanoencapsulation for food applications, classifying these method-
ologies according to top-down (TD) and/or bottom-up (BU); (ii) the principal types of
encapsulation systems; (iii) the natural plant sources of bioactive compounds of interest
for the food industry to be encapsulated, enhancing the agro-industrial by-products; (iv)
the bioavailability of the micro- and nanocapsules, presenting the various mechanisms for
the release of the bioactive compound; and (v) the main techniques used to analyse these
micro- and nanocapsules, and their respective advantages.

2. Micro- and Nanoencapsulation Methodologies

Nanoencapsulation is a process by which an active agent is coated by carrier material
in order to form capsules on the nanometric scale. The coated materials are also designated
as the core, fill, or internal phase, while the carrier materials are known as the wall material,
membrane, capsule, shell, matrix, or external phase [10].
In nanoencapsulation, two aspects are normally relevant; one is the selection of the
encapsulating material and the other is the specific encapsulation technique. For food
applications, the encapsulating materials must be “generally recognized as safe” (GRAS).
Nevertheless, it is of relevance as well to consider the encapsulated compound concentra-
tion, the stability of the capsule, its function in the food application, the target aimed for,
and the efficiency of delivery [10]. The nanocapsule can be formed by biopolymers, such as
proteins, carbohydrates, fats, and other organic and inorganic materials [1]. Emulsification,
coacervation, inclusion complexation, emulsification solvent evaporation, extraction, nano-
precipitation, electro-spraying (spray drying), and electro-spinning are the most common
encapsulation techniques used for bioactive compounds [8]. The chosen technique varies
according to the type of bioactive compound that is encapsulated, for example, whether it
is volatile or not, the size of the nano- or microcapsule, the type of shell material, and other
parameters. Nanoencapsulation is an area in constant innovation, and many recent studies
have proposed new formulations or new encapsulation systems for the preservation of
bioactive compounds with improved functionalities [10].
There is no standard technique to perform nanoencapsulation, and to choose a method,
the type and characteristics of the active compound, which will be the core of the particle,
must be taken into account; regarding the carrier material, its molecular weight, polarity,
solubility, structure, and encapsulation efficiency need to be considered, and the particle
size is also an important factor [5,10]. The principal techniques used for micro- and
nanoencapsulation are listed in Table 1. Sometimes, two or more methods can be combined,
such as emulsions used with spray drying or freeze drying.
Two approaches, the top-down and the bottom-up approaches, can be used to produce
micro- and nanocapsules. Figure 1 presents several technologies used to produce micro-
and nanocapsules according to these approaches. Figure 2 illustrates the difference between
the two approaches relative to the size of the particles: the bottom-up one consists of the
elaboration of capsules by the self-building or self-organization of molecules from small
particles (nm) to big encapsulated aggregates (µm); the top-down approach consists of
the opposite, involving the disintegration of bulk solids, liquids, or large particles (1 mm),
 Foods 2023, 12, 32 6 of 23

Foods 2022, 11, x FOR PEER REVIEW 7 of 24

Foods 2022, 11, x FOR PEER REVIEW 7 of 24
in small particles (from 1 µm down to, for example, 200 to 450 nm of gelatine hydrogel
particles [11]).

Techniques to
Figure1.1.Techniques
Figure to produce
producemicro-
micro-and nanocapsules,
and according
nanocapsules, to thetotop-down
according and bottom-
the top-down
Figure
up 1. Techniques to produce micro- and nanocapsules, according to the top-down
methodologies.
and bottom-up methodologies.
and bottom-up methodologies.

Figure 2. Size ofofthe micro- and nanocapsules (adapted with permission

permissionfromfrom[39].
[39].Copyright
Cop-
Figure2.2. Size
Figure Size ofthe
themicro-
micro-and
andnanocapsules
nanocapsules (adapted
(adaptedwith
with permission from [39]. Cop-
yright 2017, Elsevier).
2017, Elsevier).
yright 2017, Elsevier).
The top-down (TD) approach goes from a large-structure material to a
Thetop-down
The top-down (TD) approach goes from a large-structure material to a
small-structured one (TD) approach
(Figure goes from
2) through a large-structure
a size reduction andmaterial
shapingto of
a small-structured
the structure
small-structured
one (Figure 2) one (Figure
through a size 2) through
reduction anda shaping
size reduction
of the and shaping
structure throughof the structure
mechanical
through mechanical ways, such as milling, shredding, and grinding. It may use three
through
ways, suchmechanical
as milling,ways, such and
shredding, as milling,
grinding. shredding,
It may useand
threegrinding.
types of Itforces
maytouse three
disrupt
types of forces to disrupt the particles: shear, impact, and compression. TD methodolo-
types
the of forces
particles: to disrupt
shear, impact,the
and particles: shear, TD
compression. impact, and compression.
methodologies include TD methodolo-
emulsification,
gies include emulsification, solvent evaporation, and extrusion. The latter, for example,
solvent evaporation,
gies include and extrusion.
emulsification, The latter, for
solvent evaporation, andexample,
extrusion.creates small for
The latter, biopolymer
example,
creates small biopolymer particles in a solution by forcing it to pass through a nozzle into
particles in a solution
creates small biopolymerby forcing
particlesitin
toapass through
solution a nozzle
by forcing into
it to a gelling
pass throughenvironment,
a nozzle into
a gelling environment, with the size of the particles depending on the diameter of the
with the size
a gelling of the particles
environment, depending
with on the
the size of the particles
diameter depending
of the needle,onthe
theflow rate, and
diameter of the
the
needle, the flow rate, and the viscosity of the solution. Ultrasounds can be used to break
needle, the flow rate, and the viscosity of the solution. Ultrasounds can be used to break
up the polymer solution stream. Another process used is homogenization, which in-
up the polymer solution stream. Another process used is homogenization, which in-
Foods 2023, 12, 32 7 of 23

viscosity of the solution. Ultrasounds can be used to break up the polymer solution stream.
Another process used is homogenization, which involves forming an emulsion by joining
two immiscible liquids. This emulsion can be gelled by temperature management or by
adding gelling agents, with the possibility of being an oil-in-water emulsion (normally, for
proteins or polysaccharides) or a water-in-oil emulsion (hydrogels of 200–450 nm), but it
can also be a water-in-water-in-oil or a water-in-oil-in-water emulsion [11]. Hydrophilic
or hydrophobic compounds can be encapsulated by this TD methodology. However,
it requires special tools and exerts low control over the particle size and structure. It
may be applied only for some types of matrices. Furthermore, grinding and milling are
not recommended for high-value and/or sensitive bioactive compounds because of the
pressure and mechanical stress, which may induce damage [10,11].
The bottom-up (BU) methodology consists of the association of small particles (Figure 2)
through self-building and self-organization. These can be affected by pH, temperature,
the concentration of the encapsulated compound, and the ionic strengths. This approach
includes spray drying, supercritical fluid expansion, inclusion complexation, coacervation,
and nano-precipitation. These techniques consume less energy than top-down methods
and allow control over the particle size, distribution, and structural morphology [10,11].
Coacervation is the process by which two oppositely charged biopolymers interact through
electrostatic attraction, but hydrophobic interactions and hydrogen bonds may also oc-
cur [11]. Inclusion complexation is the molecular encapsulation of a bioactive molecule in
the cavity of a host molecule. Drying is another technique, and it can be spray drying or
freeze drying. Spray drying consists of atomizing a solution of biopolymers and bioactive
compounds into fine droplets, forming microspheres or microgels with a size of 1 to 10 µm.
Freeze drying includes freezing, sublimation, and desorption, requiring capsules with
a high porosity, which affects the stability of the enclosed bioactive component and its
retention efficiency. In a fluid gel formation, which includes thermal and ionic gelation,
capsules are formed by applying shear forces on a biopolymer solution [11].
From a critical analysis of the various techniques to carry out micro- and nanoencap-
sulation (Table 1), it is possible to conclude that most methodologies begin by producing
an emulsion through the junction of immiscible liquids or the solubilisation of solids, and
then a specific technique is applied. For example, techniques such as nanoemulsion, ultra-
sonication, and freeze drying [40]; ionic gelation, ultrasonication, and freeze drying [41]; or
ionic gelation and freeze drying [42] may be simultaneously used.
The literature underline that some techniques are used in both top-down and bottom-
up methodologies, such as ultrasonication, spray drying, and freeze drying. However,
there are others, such as ionic gelation and phase temperature inversion (some authors
call it “fluid gel formation”, e.g., Joye et al. [11]), for which the classification as a TD or
BU approach is non-consensual. Based on the principle of the nature, which consists of
a powder solubilizing in a solvent, and taking into consideration that these methods use
temperature inversion or ionic strength to form a gelling substance, they were classified as
BU methodology in the present review work.
The TD methodology involves the use of precise tools and specified equipment, which
allow size reduction and structure shaping. However, it is a more expensive technique
due to the costs of the equipment and its maintenance. Another issue is the elaboration
of particles with a well-defined structure. Furthermore, grinding and milling may not be
suitable for sensitive bioactive ingredients. While using a BU approach, the aggregates are
built by the self-organization of the molecules, and this is influenced by several factors. This
approach allows the production of very fine particles, thus controlling the size, morphology,
and physical state. In addition, the risk of contamination is significantly reduced compared
with the TD approach, and BU methods require higher energy than TD ones [11].
Another important issue is how to choose the technique to use, and here it may be
suggested that the final function of the encapsulated product, such as gelling or in the form
of a powder or a solution for spraying or dipping the food product, is most likely what
dictates this selection.
 form of a powder or a solution for spraying or dipping the food product, is most likely
what dictates this selection.
Either technique of micro/nanocapsulation must allow a high loading capacity, a
Foods 2023, 12, 32 high encapsulation efficiency, and the stability of the encapsulated system, while 8 of 23
providing a long shelf life, biocompatibility, and the desired release characteristics of the
encapsulated active compound [10].

3. Nanoencapsulation Either technique of micro/nanocapsulation must allow a high loading capacity, a high
Systems
encapsulation efficiency, and the stability of the encapsulated system, while providing a
Encapsulation
longcan belife,
shelf affected by the size,and
biocompatibility, shape, and internal
the desired releasestructure of the cap-
characteristics of the encapsulated
sules, their physicochemical stability,
active compound [10]. and their entrapment and release behaviours, with
their biological activity being important as well. It is possible to associate the nanocapsule
to the methodology that is used to make
3. Nanoencapsulation the aggregates.
Systems
Nowadays, several techniquescan
Encapsulation arebeavailable
affected for producing
by the nanocapsules,
size, shape, and internalasstructure
well as of the capsules,
several materials to use as the shell of these aggregates, allowing various
their physicochemical stability, and their entrapment and release behaviours, types of with their
nanocapsules. The principal types are mentioned in the following text and are illustrated
biological activity being important as well. It is possible to associate the nanocapsule to the
in Figures 3 and 4. The characteristics
methodology that is usedof to
the compound
make to be encapsulated and the ob-
the aggregates.
jective for its use condition
Nowadays,the choice of the
several encapsulation
techniques system, e.g.,
are available the polaritynanocapsules,
for producing of the as well
compound andasitsseveral
hydrophilicity
materialsortolipophilicity. Thereofisthese
use as the shell a high variety ofallowing
aggregates, carriers invarious types of
nanoencapsulation, natural compounds
nanocapsules. The principalor synthetic
types arepolymers,
mentionedwith principal
in the character-
following text and are illustrated
istics in the textin
below and illustrated in the next figures.
Figures 3 and 4. The characteristics of the compound to be encapsulated and the objec-
tive for its use condition the choice of the encapsulation system, e.g., the polarity of the
compound and its hydrophilicity or lipophilicity. There is a high variety of carriers in na-
noencapsulation, natural compounds or synthetic polymers, with principal characteristics
in the text below and illustrated in the next figures.

Figure 3. Some important nanocarriers for bioactive compounds used in food applications (created
with BioRender.com, accessed on 4 December 2022).

There are several types of nanoencapsulation systems:

Figure 3. Some important nanocarriers
Reservoir for bioactive
and matrix (Figurecompounds used in
3): the active food applications
compound, (createdby a polymeric
surrounded
with BioRender.com, accessed on 4 December 2022).
membrane, is in a single hollow chamber in the reservoir system, which is called the
capsule, single core, mono core, or core shell. The active compound is distributed in the
encapsulated material, but it can also exist on the surface of the matrix system, called the
sphere or particle. Both the reservoir and matrix may be combined, resulting in a multilayer
form or coated matrix [5,10,43].
Emulsion (Figure 4): there are two immiscible phases in an emulsion: the disperse
phase and the continuous one. The disperse phase droplets can entrap the bioactive
compound and the continuous phase protects the loaded droplets from the environment.
Two types of this emulsion are the water-in-oil and oil-in-water types. The disadvantages of
these are their thermodynamic instability and susceptibility to destabilization. Multilayer
emulsions, multiple emulsions, and nano emulsions can be formed [5,10,44].
 Foods 2022, 11, x FOR PEER REVIEW

Foods 2023, 12, 32 9 of 23

Figure 4. Nanostructures and nanocarriers for some nanoencapsulated bioactive compounds

Figure 4. Nanostructures and nanocarriers for some nanoencapsulated bioactive com
(adapted with permission from [25]. Copyright 2010, Elsevier).
(adapted with permission from [25]. Copyright 2010, Elsevier).

Lipid nano-particles (Figure 3): in preparation, this system is similar to the emulsion
There are several types of nanoencapsulation systems:
systems, with lipophilic active compounds being spread in a mixture of solid and liquid
Reservoir and matrix (Figure 3): the active compound, surrounded by a po
forms of lipids with emulsifiers. Nanoparticles can be composed of solid lipids and
membrane,
carriers can be is in lipids.
nanostructured a singleTo hollow
produce chamber in thehigh-energy
these particles, reservoir system, which is cal
consumption
capsule, single core, mono core, or core shell. The active
may be used, such as high-pressure homogenization, micro-fluidization, or sonication compound is distributed
encapsulated
methods; low-energy material, but
consumption it can also
methods, suchexist
as theonphase
the surface
inversionof the matrix system, ca
temperature,
sphere
microemulsion, or particle.
solvent diffusionBoth the reservoir
or injection, and matrixfluid
and supercritical maytechnology,
be combined, mayresulting
also in a
layer
be used [10,44]. form or coated matrix [5,10,43].
Emulsion
Lipid vesicular carriers(Figure
(Figures4): there
3 and 4):are two the
among immiscible phases in
diverse vesicular an emulsion:
carriers, such the d
as niosomes,phase and the
bilosomes, continuous ethosomes,
transferosomes, one. The disperse phase droplets
and phytosomes, liposomescanare
entrap
the the b
most used incompound
food. Liposomes
and thecontain a hydrophilic
continuous head (polar)
phase protects and a hydrophobic
the loaded droplets fromtailthe enviro
(non-polar),Two
acting as a semi-permeable membrane, which separates the inner aqueous
types of this emulsion are the water-in-oil and oil-in-water types. The disadv
phase from ofthethese
external
are water phase. The methods
their thermodynamic used toand
instability produce liposomestoare
susceptibility high-
destabilization
pressure homogenization, micro-fluidization, electro-spraying, supercritical carbon
layer emulsions, multiple emulsions, and nano emulsions can be formed [5,10,44] dioxide
technology, and ethanol injection [10,44].
Lipid nano-particles (Figure 3): in preparation, this system is similar to the em
Hydrogel particles (Figure 4): this system is a three-dimensional and cross-linked
systems, with lipophilic active compounds being spread in a mixture of solid and
polymeric network that is able to quickly absorb water and to hold it in less favourable
forms of lipids with emulsifiers. Nanoparticles can be composed of solid lipids a
conditions (heat, pressure). Natural polymers have attracted more interest than synthetic
riers can be nanostructured
ones. Polysaccharide-based lipids. polymers
and protein-based To produce arethese particles,
the most used high-energy
to prepare consu
may be used, such as high-pressure homogenization, micro-fluidization, or son
methods; low-energy consumption methods, such as the phase inversion temp
Foods 2023, 12, 32 10 of 23

hydrogel particles through gelation. These techniques allow the encapsulation of both
hydrophilic and hydrophobic bioactive compounds [10,44].
Biopolymer-based systems (Figure 3): this system consists of polyelectrolyte com-
plexes formed by electrostatic interactions among oppositely charged polymers, such as
carrageenan and protamine, solubilizing the nutraceutical compounds in either a positively
or negatively charged biopolymer. Biopolymer substances, such as amylose, starch, pectin
carrageenan, and chitosan, can be used.
Protein carbohydrates: protein carbohydrates are self-built structures composed of
anionic polysaccharide and cationic protein surface groups, which may be produced by
thermal denaturation or aggregation [44].
Molecular inclusion complexes (Figures 3 and 4): molecular inclusion complexes
are other encapsulated forms that are less used, such as cyclodextrins, but there are also
nanofibres, nanotubes, and micelles [10].
The stability of a nanoencapsulation system may be inferred through the potential
zeta, which is a physical property of particles in colloidal dispersions, influenced by the
nanocapsule composition and the medium surrounding them [45].

4. Micro- and Nanocapsules from Natural Products

The use of “generally recognized as safe” (GRAS) materials is important for producing
safe nanocapsules for food applications, along with the nutritional quality and stability.
Polysaccharide-based carrier agents are natural carbohydrate polymers composed of var-
ious monosaccharides with glycosidic bonds and can be found in plants, animals, algae,
and microorganisms. Some examples are starches from plants and the dextrins, maltodex-
trins, and cyclodextrins used to encapsulate hydrophobic bioactive compounds. Another
example is cellulose, but it presents the limitation of being poorly soluble in water. Other
compounds are pectin, chitosan, alginate, and gums. Upadhyay et al. [46] studied Cananga
odorata essential oil nanoencapsulated with chitosan, forming a nano-emulsion. They
concluded that it inhibited the growth of Apergilus flavus and improved the antioxidant
activity. These results demonstrated that this formulation improved the shelf life of stored
food against Apergilus flavus, which produces aflatoxin B1, and lipid peroxidation, turning
natural nanocapsules into good candidates for edible coating formulations.
Protein-based carriers, which have a high nutritional value, may be GRAS materials.
An example is whey protein, which has emulsifier proprieties; the caseins present in milk
can constitute an excellent emulsifier. Good sources of edible proteins are gelatines, soy
proteins, cereal (wheat, barley, and corn) proteins, potato protein, and pulse proteins
(peas, chickpeas, lentils, beans, and lupins), and they present a high nutritional value.
Another group of compounds with interest is the lipid-based carriers, fats, and oils. They
may be polar lipids, such as monoglycerides and phospholipids, or nonpolar lipids, such
as triacylglycerol and cholesterol. They are good emulsifiers that may be used in the
encapsulation of bioactive compounds [10,45,47].
Natural resources are widely used as raw materials in industry. Nowadays, the
reuse of natural bioactive compounds from by-products from the agro-food industry has
increased, and under a circular bioeconomy perspective, these products are not wastes,
but a source of economic-value compounds with a variety of applications. In some cases,
by-products with low economic interest, but that are abundant, may also be used. The
rational use of agro-industrial by-products in the nanobiotechnology field aims for the
development of novel products and high-value-added processes. These agro-industrial
by-products include fruit peels and seeds, pomaces, and straws, and they may be used as a
source of high-value compounds, such as flavonoids, lycopene, and polyphenols. The main
advantages of agro-industrial by-products are their abundance, low cost, biocompatibility,
biodegradability, and, often, bioactivity. In this way, bioactive compound delivery systems
may be obtained with relatively low production costs and environmentally sustainable
management, due to the reuse of by-products [48].
Foods 2023, 12, 32 11 of 23

Actually, around 1.3 billion tonnes of food are lost or wasted globally, costing USD 900
billion along the whole supply chain [49]. For instance, according to the World Bank, a 1%
decrease in post-harvest losses might result in a USD 40 million reduction in this loss [50]. A
more efficient use of agro-industrial by-products, considered residues, would most certainly
contribute as well to reduce this loss, contributing at the same time to a circular economy
by the conservation of the product value, materials, and resources in the economy for a
long period with reduced waste generation, according to the Circular Economy Action
Plan [49]. The extraction from these residues and the further micro- and nanoencapsulation
of bioactive compounds with economic value for the food industry would represent a
valorisation and a contribution to sustainable agro-food residue management.

4.1. Micro- and Nanoencapsulation for Functional Ingredient Delivery in Food Applications
Wrong lifestyle choices often contribute to the development of obesity, type 2 diabetes,
and cardiovascular diseases. An adequate diet through functional ingredients could man-
age prevention at an early stage and before a therapeutic intervention. However, some of
these ingredients cannot permeate into the small intestine in a sufficient concentration for
efficacy without an efficient oral delivery system. Nowadays, there are various solutions
to respond to these problems, such as using low-permeable hydrophilic peptides and
macromolecules (nanoparticles), or intestinal permeation enhancers, for these mucolytics
appear as a solution and with potential application. Gleeson et al. [44] found that there is
an opportunity for the nutraceutical industry to explore the progress of the pharmaceutical
industry in drug delivery systems. Excipients or substances already tested in humans have
a high potential to be used in formulations in a delivery approach. This might improve the
solubility, stability, or permeability of those molecules. In diet, the bioavailability of bioac-
tive compounds is a challenge, mainly for hydrophobic compounds. Nanoencapsulation
presents itself as a solution for isolating a bioactive compound from its natural environment,
e.g., a fruit or vegetable, and incorporating it into a suitable delivery system [51]. The tech-
nological use of edible nanocapsules might serve to preserve bioactive compounds that are
adequate for food applications, protecting the antioxidant and antimicrobial characteristics
of these compounds (Table 2).

Table 2. Micro- and nanoencapsulated bioactive compounds, plant sources, and functionalities for
food applications.

Bioactive Compound Plant Source Micro/Nanoencapsulation Function Reference

(Core) Method
Cadinene, camphor,
Cinnamomum zeylanicum
cinnamaldehyde, Blume essential oil EO [52,53]
eugenol
Carnosic acid, carnosol,
rosmadial, Rosmarinus officinalis L.
rosmaridiphenol, EO Oil-in-water [52,54]
rosmarinic acid emulsification; spray
drying Antimicrobial
Carvacrol, γ-terpinene, activity
p-Cymene, thymol, Origanum vulgare L. EO [52,55]
β-caryophyllene
Phenolics such as Foeniculum vulgare var.
apigenin, quercetin dulce (Mill.) EO [52,56]

Menthol, menthone, Peppermint EO; Microemulsion and

menthofuran, menthyl Tragacanth gum (shell) ultrasonication [57]
acetate, piperitone

Carvone, dillapiol, Antimicrobial,

Anethum graveolens L. EO Emulsion and freeze anti-aflatoxigenic,
drying [58]
limonene antioxidant activities
Foods 2023, 12, 32 12 of 23

Table 2. Cont.

Bioactive Compound Plant Source Micro/Nanoencapsulation Function Reference

(Core) Method
Anethole, estragole, Ionic gelation and
Pimpinella anisum EO [59]
fenchone ultrasonication
Carvacrol Thymus capitatus EO Nano-precipitation [60]
Carvacol, cymene,
Origanum Phase inversion
thymol, β-fenchyl vulgare EO temperature [30]
alcohol, γ-terpinene
Carvacrol, γ-terpinene,
thymol, o-cymene, Zataria multiflora EO Ionic gelation Antifungal [28,61]
α-pinene activity
Elemicine, myristicine, Myristica fragrans Houtt.
EO Ionic gelation [62]
thujano
Eugenia caryophyllata and Ionic gelation and
Eugenol [63]
Ocimum sanctum EO ultrasonication
Ionic gelation
Linalool Homalomena aromatic EO [42]
and freeze drying

Linalool, methyl chavicol Ocimum sanctum EO Emulsion and freeze

drying [64,65]

Menthol, menthone, Self-assembly and

Mentha piperita EO [66,67]
menthofuran, pulegone ultrasonication
Cadinene, caryophyllene,
cymene, limonene, Schinus molle L. EO Ionic gelation [68]
phellandrene
Camphor Ocimum canum EO Nano-emulsion,
ultrasonication, and [40]
Eugenol Ocimum sanctum EO freeze drying
Estragole Ocimum basilicum EO
Citral Cymbopogon citratus EO Ionic gelation,
ultrasonication, and Antifungal, [41]
Geraniol Lippia rugosa EO anti-aflatoxigenic
freeze drying
Terpineol Melaleuca alternifolia EO activities
Citronellyl formate, Pelargonium graveolens Emulsion and
EO ultrasonication [36]
linalool, menthone
Cuminaldehyde, cymene, Bunium persicum (Boiss.) Ionic gelation [69]
terpinene terpinen-7-al B. Fedtsch EO
Linalool Cananga odorata EO Ionic gelation and freeze
[70]
Methyl cinnamate Zanthoxylum alatum EO drying
Thymol Thymus vulgaris EO
Anti-aflatoxigenic,
Anethole, estragole Illicium verum EO Ionic gelation [71]
antioxidant activities
Anti-mycotoxigenic
Eugenol Clove EO Electrospray [72]
(antifungal)
Benzyl acetate, linalool Conanga odorata EO Ionic gelation Antifungal, [46]
Carvacrol Petroselinum crispum EO Nano-emulsion antioxidant activities [73]
Antioxidant activity,
Spray drying colourant (fortified [74]
Curcuma longa L. root rice)
Curcumin
Emulsion and
ultrasonication Food colourant [75]

EO—essential oil.
Foods 2023, 12, 32 13 of 23

From a critical analysis of the different micro- and nanoencapsulated bioactive com-
pounds and related functionalities (Table 2), it is possible to conclude that the main purpose
of using these compounds is to extend the shelf life of food products, due to their an-
timicrobial (mainly antifungal) and antioxidant activities. The principal technique of
micro/nanoencapsulation is ionic gelation, probably because it is easy to apply in an-
timicrobial in vitro tests. Therefore, further studies are required on the application of
encapsulates to the final food products. The studies reported in the literature are essentially
in vitro studies on the effects of nano-aggregates on microorganisms; only a few studies
apply to real food products.
As already mentioned in this review, there are nanocapsules that carry natural com-
pounds, mainly essential oils, but also extracts from plants and fruits, for food applications,
as antimicrobials and antioxidants. However, there are only few studies on nanocapsules
carrying natural compounds from agricultural by-products (Table 3).
In addition, other types of compounds from by-products can be used in the shell
composition of the nanocapsule. As mentioned above, soy, cereal, potato, and pulse
proteins, polysaccharides, and lipid-based carriers are some examples of such compounds
that may be used to encapsulate bioactive compounds. Table 3 shows some examples of
shell materials, which can be obtained from agri-food by-products.
It would be of the uttermost importance to carry out more research work on the
extraction and preservation by micro- and nanoencapsulation of identified bioactive com-
pounds from agro-industrial by-products. As previously mentioned, these agro-industrial
by-products are actually under-used (e.g., as animal feed), often abundant, of low cost, and
contain high-value compounds with antimicrobial and antioxidant properties, presenting
a high potential for further re-use in the food industry. On the other hand, the economic
features of agro-industrial by-product re-use have not yet been fully explored. There-
fore, all these research studies would contribute to advances towards a circular economy
and sustainability.

Table 3. Micro- and nanoencapsulated bioactive compounds from agro-industrial by-products for
the shelf-life extension of food products.

Micro/Nanoencapsulation
Bioactive Compound Source/By-Product Function References
Method; Shell
Acerola/unused pulp;
Coumarin, resveratrol, Emulsion evaporation
guava/peel; passion [76]
quercetin solvent
fruit/seeds
Antimicrobial and
Emulsion and freeze antioxidant activities
Hesperidin, naringin,
drying;
narirutin, Orange/peel [77]
Shell: maltodextrin, whey
neohesperidin
protein isolate
Extrusion;
Anthocyanins Mulberry/pomace [78]
Shell: calcium alginate
Anthocyanins, ascorbic
Ultrasonication;
acid, carotenoids, Cherry/pomace [79]
Shell: maltodextrin
flavanols, flavonols
Ultrasonication and freeze Antioxidant activity
Anthocyanins, ascorbic
drying;
acid, carotenoids, Sour cherry/pomace [79]
Shell: maltodextrin or
flavanols, flavonols
arabic gum
Ascorbic acid,
carbohydrates, Jujube/pulp and seed Ionic gelation;
[29]
phenolics, riboflavin, extracts Shell: chitosan
thiamine
Foods 2023, 12, 32 14 of 23

Table 3. Cont.

Micro/Nanoencapsulation
Bioactive Compound Source/By-Product Function References
Method; Shell
Ascorbic acid,
flavonoids (eriocitrin Emulsion;
hesperidin, naringin, Orange and lemon/peel Shell: maltodextrin or [80]
narirutin), phenolics, arabic gum
pectin
Cyanidin, delphinidin,
malvidin, pelargonidin, Black carrot/pomace Emulsion, ultrasonication [81]
peonidin, petunidin
Nanoemulsion;
Flavonoids, phenolics Fruit pomegranate/peel Shell: maltodextrin, whey [82]
protein isolate
Spray drying;
Lycopene Tomato/pomace [83]
Shell: arabic gum or inulin
Monoterpene and
sesquiterpene
hydrocarbons Industrial hemp/essential Nanoprecipitation;
Antioxidant activity [84]
(α-pinene, myrcene, oils (Cannabis sativa L.) Shell: alfalfa protein isolate
α-humulene,
(E)-caryophyllen)
Phenolics, flavonoids, Emulsion, ultrasonication;
Citrus
flavones (nobiletin), Shell: lipids
(mandarin, lemon, lime, [85]
polymethoxyflavones, (medium-chain
sweet orange)/pomace
(tangeretin, nobiletin) triglycerides)
Phenolics
(p-hydroxybenzoic acid, Emulsion;
Blueberry/pomace [86]
epicatechin gallic acid), Shell: whey proteins
anthocyanins
Polyphenols Apple/pomace Ultrasonication [87]
Spray drying;
Resveratrol Grape wine/pomace Shell: maltodextrin and [88]
milk proteins
Emulsion and freeze
Tyrosol Olive/pomace [89]
drying

4.2. Nanoparticles with Natural Compounds from Agriculture By-Products

Searching for the use of by-products in nanotechnology brings along another issue
that should be considered in this review: the use of nanoparticles from different sources,
such as gold, silver, platinum, zinc, or iron, with these particles being coated with natural
compounds from agricultural wastes [90,91]. The use of these by-products is usually
related to antioxidant activity, while reinforcing the antimicrobial activity. Normally, the
production of these nanoparticles is studied at variable conditions (temperature, pH) in
order to optimize their antimicrobial and/or antioxidant activities [90,92].
The production of nanoparticles coated with natural bioactive compounds is very in-
teresting and has been explored by several authors. For example, authors have investigated
the use of silver antimicrobial nanoparticles in combination with grape seeds and pomace
extracts [91,93], orange peel [91,92], persimmon seeds, peel and calyx extracts [94], Persea
americana peel, Beta vulgaris peel and Arachis hypogaea shell [90], Cocos nucifera L. shell [95],
sugar cane bagasse [96], banana peels extract [97], and mango peel extract [98].
Although most examples of nanoparticles are from inorganic materials, some may
also be lipid-, protein-, or polysaccharide-based (see Section 3, nanoencapsulation systems,
above). For example, Angourani et al. [99] used zein (corn protein) nanoparticles to entrap
Foods 2023, 12, 32 15 of 23

rosemary essential oil (entrapment efficiency ca. 71%) in order to prevent evaporation and
preserve its bioactivity. Bilal et al. [100] suggested the use of starch, cellulose, and pectin as
the main types of polysaccharide-based nanoparticles for food applications.

5. Micro- and Nanocapsule Bioavailability

Recently, research has focused on the development of new nanocarriers with potential
applications in the formulation of functional foods. However, only a few products have
been commercialized. Among all the nanocarriers studied, only five were approved by
the Food Safety European Authority [101]; these included inorganic materials (iron, silver,
calcium, magnesium, selenium, and titanium oxide) for nanoparticles, and organic nano-
materials (lipid-, protein-, and polysaccharide-based). This is because a major portion of
the tests were in vitro and only a few were in vivo and, therefore, more of the latter studies
were required to demonstrate the efficiency and safety of such nanoparticles/capsules [101].
The rule of five [101] outlines that 90% of the oral drugs in the pharmaceutical area
must obey three out of four of the following guidelines, which allows compounds to be
obtained that have a good oral bioavailability:
Molecular weight (MW) ≤ 500 Da;
Logarithm of its partition coefficient (log(P)) ≤ 5;
Hydrogen bond acceptors (HBA) ≤ 10;
Hydrogen bond donors (HBD) ≤ 5.
Some authors also add a polar surface area (PSA) ≤ 140 Å2 and a number of rotatable
bonds (NRotB) ≤ 10. These guidelines were constructed based on the results of oral
bioavailability [101,102].
The absorption of bioactive nanocapsules is conditioned by the properties of the
bioactive compounds, the nanocapsule used, and the environmental conditions. Table 4
summarizes the principal steps of the absorption of nanoencapsulated compounds.

Table 4. Nanocapsule absorption in the human body ([103,104]).

Nanocapsule Degradation for

Body Target Example of Nanocapsule Goal
Release of Bioactive Compounds
Mechanical disruption, pH and
Hydrogel,
Mouth temperature changes, enzymatic Release of flavour
biopolymeric particles
degradation (1 to 5 min)
Molecular complexes:
pH decrease, ionic strength changes,
protein-based hydrogel particles, Release of acid-stable
Stomach mechanical disruption, enzymatic
protein-based biopolymeric nutrients
degradation (30 min to 4 h)
particles
Hydrogel and biopolymeric
pH increase, ionic strength changes, Release and protection of
Small intestine particles produced with digestible
enzymatic degradation (1 to 2 h) acid-sensitive nutrients
proteins and polysaccharides
pH increase, enzymatic
Dietary fibre-based, hydrogel
Colon degradation, bacterial degradation Delivery of probiotics
particles, biopolymeric particles
(12 to 24 h)

There are various mechanisms for the release of bioactive compounds from nanocap-
sules: diffusion, dissolution, erosion, swelling, osmosis, degradation, and fragmenta-
tion [103,105]:
Diffusion: the diffusion of a bioactive compound from the interior to the exterior of
an encapsulation system depends on the solubility in the encapsulated system and its
permeability through the capsule material. The release rate of bioactive compounds can
be affected by several factors, such as the bioactive compound characteristics (molecular
weight, polarity, and vapour pressure); it depends also on the encapsulation system itself
(polarity, physical state, interactions, and rheology).
Foods 2023, 12, 32 16 of 23

Dissolution: two types of dissolution can be defined, with the first one being the
encapsulation–dissolution-controlled system, in which bioactive compounds are encapsu-
lated in dissolving materials and the dissolution rate is controlled by the solubility of the
bioactive compounds and the physico-chemical proprieties of the carrier. In the second
type, the matrix–dissolution-controlled system, the bioactive compounds are distributed
uniformly through the particle, having an influence on the dissolution rate.
Erosion: this release mechanism happens when the encapsulated system faces a
specific environmental condition, the chemical degradation of the particle matrix, causing
the release of the bioactive compound. It may be caused by various factors, such as
physical (high temperatures), chemical (strong acids or bases), or enzymatic. There are
two types of erosion: bulk erosion, where the degradation occurs throughout the entire
particle, and surface erosion, where the degradation only occurs on the surface of the
encapsulated compound.
Swelling: the release of bioactive compounds happens when the capsule swells because
of the solvent absorption; this release mechanism may be controlled by the selection of the
polymeric matrix and the environmental conditions, such as temperature and pH.
Osmosis: the release begins when an osmotic pressure is created by water absorption,
triggering the release of bioactive compounds. Ultimately, this type of release mechanism
is comparable with a solvent-activated release (swelling mechanism) because the particles
absorb the solvent until rupture and then release the bioactive compounds.
Degradation: degradation is the disruption of biomaterials by biological systems
(microorganisms). The core compounds dispersed in the polymer matrix are released after
the biodegradation of the polymer.
Fragmentation: the bioactive compounds are released from the encapsulation system
when this is ruptured, due to environmental factors, such as pressure, pH, or enzymatic.
The release of nanoencapsulated bioactive compounds depends on the type of the
bioactive compound and on the encapsulated system. The properties of bioactive com-
pounds, such as the solubility, diffusivity, interior–exterior concentration gradient across
the particle, interactions (repulsion forces between the bioactive compound and the encap-
sulation system), entrapment type of the bioactive compound inside the carrier, and size of
the particle, will affect the release profile. The encapsulate properties can also condition the
release of the bioactive compounds: the size, shape, structure, porosity, and composition
can affect the release. Small nanoparticles tend to create an initial crack release followed by
a slower one; however, big nanoparticles are degraded more slowly and display a slower
diffusion of the bioactive compounds. The hydrophilicity or the hydrophobicity of a poly-
mer may also cause strong interactions between the capsule and the bioactive compound,
reducing the release rate. The oil phase of emulsion-based delivery systems controls the
oil droplet polarity and increases the polymer molecular weight, with a high molecular
weight displaying a reduced decomposition rate and causing an extended constant release
of the bioactive compound over time. Some encapsulated bioactive compounds are soluble
in either the oil or water phases and, as a consequence, they can leave the oil droplets when
the emulsion is diluted in water. The environmental conditions, such as temperature, agita-
tion, pH changes, and the presence of ions, can control the profile release of the bioactive
compounds. For example, hydrogels are temperature-sensitive and pH-responsive. Other
factors that can control the bioactive compound release are ultrasounds, light, oxidation, a
reduction in the potential, and enzymes [103].
The effectiveness of nanocapsules requires evaluation, since they cannot be controlled
with precision due to the complex processes of absorption, distribution, metabolism, and
excretion [106].

6. Analysis of the Micro- and Nanocapsules

Nowadays, several techniques are available to analyse the structure of micro- and
nanoencapsulated aggregates. Table 5 describes some of them, as well as their advantages
in comparison to others, and what is possible to analyse by each technique.
Foods 2023, 12, 32 17 of 23

Table 5. Techniques to analyse the nanocapsules.

Encapsulated Bioactive
Technique of Analysis Advantages Objectives Reference
Compound
Size, morphology,
High reproducibility;
Volatile and non-volatile loading capacity,
Spectroscopy UV/Vis, GC, versatile approach to
bioactive compounds entrapment efficiency, [107]
GC-MS, LC, LC-MS, HPLC performing quantitative
of food stability, structural
analyses
composition
Non-destructivity;
non-invasiveness;
Characterization of
Liquid, solid, and Nuclear magnetic high reproducibility;
nanocapsules in [108,109]
semi-solid samples resonance (RMN) quantitative determination;
different environments
no compound separation
before analysis
Easy preparation of Particle size, particle
Chitosan, folic acid, Dynamic light scattering samples; can measure size distribution, and
[110]
vitamin D3 (DLS) particles with less than 1 relaxation in complex
nanometre fluids
Lipid-based,
Study of the
protein/polysaccharide- Scanning electron Scale of nanoparticles
morphology and [111]
based, nanofibers, microscopy (SEM) evaluated
surface structure
nanotubes
Characterization of the
High-resolution scanning
Caranga odorata essential oil High sensitivity and nanocapsules;
electron microscopy
encapsulated in chitosan; reproducibility; identification of the
(HR-SAM),
casein hydrolysate HR-SAM allows the functional groups and [46,112]
Fourier-transform infrared
encapsulated in matrix-type structure of covalent interactions;
spectroscopy (FTIR),
maltodextrin particles to be seen study of the surface
X-ray diffraction (XRD)
morphology
Very high scanning
Study of the surface
Atomic force microscopy resolution; topological
and structure of the [113]
(AFM) image and nano-chemical
nanocapsule
analysis
X-ray photoelectron High sensitivity and Surface
Encapsulated systems [114]
spectroscopy (XPS) accuracy characterization
Loading capacity,
Confocal laser scanning observation of
Non-destructivity [115]
microscopy three-dimensional
internal structures
GC—gas chromatography, LC—liquid chromatography, MS—mass spectrometry, HPLC—high-performance
liquid chromatography.

7. Conclusions
The absorption of nutraceuticals in the human body increases with the use of micro-
and nanocapsules and the protection of bioactive compounds, with a better control release
being the major advantages of these systems. An attempt towards the optimization of
the use of micro- and nanocapsules in food applications has been carried out over time.
This review comprises a critical analysis of the different methodologies for performing
micro- and nanoencapsulation for food applications, classifying them according to top-
down (TD) and/or bottom-up (BU); the principal types of encapsulation systems; the
natural plant sources, including agro-industrial by-products, of bioactive compounds of
interest for the food industry to be encapsulated; the bioavailability of the micro- and
nanocapsules; and the main techniques used to analyse them. It was possible to conclude
that most methodologies of encapsulation begin by producing an emulsion, and then
another technique is applied. Some techniques may be used in both TD and BU approaches,
Foods 2023, 12, 32 18 of 23

but others are not consensually classified. It is suggested that the final function of the
encapsulated product is likely to dictate the selection of the micro/nanoencapsulation
technique to be used. It was possible to conclude, as well, that among different food
applications, the main focus of micro- and nanocapsuled bioactive compounds from plant
sources, including agro-industrial by-products, is to extend the shelf life of food products,
given their antimicrobial and antioxidant activities. Most studies have been performed
in vitro, with the principal micro/nanoencapsulation technique applied being ionic gelation.
Therefore, more studies on real food products and in vivo studies need to be carried out. In
addition, research work on the use of encapsulated natural bioactive compounds obtained
from agro-industrial by-products must be further reinforced, as it presents a high potential
in food applications and in the food industry, and it may be an available economical
alternative towards a circular economy, with sustainability for the natural ecosystem.
Finally, the release of micro/nanoencapsulated bioactive compounds depends on several
factors and the effectiveness of the nanocapsule requires evaluation, as it cannot be precisely
controlled given the complex processes involved.

Author Contributions: Conceptualization, R.M.S.C.M., A.M.M.B.M.; initial draft preparation,

A.M.M.B.M., V.F.R.M.; writing, V.F.R.M.; writing—review and editing, A.M.M.B.M.; review, R.M.S.C.M.,
M.E.P.; supervision, A.M.M.B.M. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Acknowledgments: This work was supported by National Funds from FCT - Fundação para a
Ciência e a Tecnologia through Project UIDB/50016/2020. The first author thanks FCT for the PhD
research grant, reference UI/BD/152825/2022.
Conflicts of Interest: The authors declare no conflict of interest.

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