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This journal is c The Royal Society of Chemistry 2012 Chem. Soc. Rev.
Cite this: DOI: 10.1039/c2cs35088b
Layer-by-layer assembly of microcapsules and their biomedical
applicationsw
Weijun Tong, Xiaoxue Song and Changyou Gao*
Received 22nd March 2012
DOI: 10.1039/c2cs35088b
Nanoengineered multifunctional capsules with tailored structures and properties are of particular
interest due to their multifunctions and potential applications as new colloidal structures in
diverse fields. Among the available fabrication methods, the layer-by-layer (LbL) assembly of
multilayer films onto colloidal particles followed by selective template removal has attracted
extensive attention due to its advantages of precise control over the size, shape, composition, wall
thickness and functions of the obtained capsules. The past decade has witnessed a rapid increase
of research concerning the new fabrication strategies, functionalization and applications of this
kind of capsules, particularly in the biomedical fields such as drug delivery, biosensors and
bioreactors. In this critical review, the very recent progress of the multilayer capsules is
summarized. First, the advances in assembly of capsules by the LbL technique are introduced
with focus on tailoring the properties of hydrogen-bonded multilayer capsules by cross-linking,
and fabrication of capsules based on covalent bonding and bio-specific interactions. Then the
fabrication strategies which can speed up capsule fabrication are reviewed. In the following
sections, the multi-compartmental capsules and the capsules that can transform their shape under
stimulus are presented. Finally, the biomedical applications of multilayer capsules with particular
emphasis on drug carriers, biosensors and bioreactors are described (306 references).
1. Introduction
The capsules have great applications in fields of medicine,
catalysis, cosmetics and so on. Nanoengineered multifunctional
capsules with tailored structures and properties are of special
interest due to their potential applications and fundamental
importance as new colloidal structures. Particularly, this type of
MOE Key Laboratory of Macromolecular Synthesis andFunctionalization, Department of Polymer Science and Engineering,Zhejiang University, Hangzhou 310027, China.E-mail: cygao@mail.hz.zj.cn; Fax: +86-571-87951108;Tel: +86-571-87951108w Part of a themed issue on supramolecular polymers.
Weijun Tong
Weijun Tong is currently anassociate professor of materialsscience at Zhejiang University.He obtained his PhD inmaterials science in 2007under the supervision of Prof.Changyou Gao at ZhejiangUniversity, China and Prof.Helmuth Mohwald at Max-Planck-Institute of Colloidsand Interfaces, Germany. Hismain scientific interests are inthe areas of supramolecularassembly, microcapsules,functional colloids and theirapplications in biomaterials.
Changyou Gao
Changyou Gao is currently aprofessor of materials scienceat Zhejiang University, awinner of the National ScienceFund for Distinguished YoungScholars of China, and aCheung Kong Scholar ofMinistry of Education ofChina. He obtained his PhDin polymer chemistry andphysics in 1996 under thesupervision of Prof. JiacongShen at Jilin University,China. His research interestsinclude self-assembled micro-capsules, nano and colloid
biomaterials and their interaction with cells, biomaterials fortissue regeneration and cell migration.
Chem Soc Rev Dynamic Article Links
www.rsc.org/csr CRITICAL REVIEW
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Chem. Soc. Rev. This journal is c The Royal Society of Chemistry 2012
capsules may supply revolutionary solutions to the problems
in biomedical fields, including but not limited to therapeutic
delivery and diagnostics.1,2 One of the promising methods
which can fabricate such a kind of capsules is layer-by-layer
(LbL) assembly3,4 of multilayer films onto colloidal particles,
followed by selective core removal (Fig. 1).5,6 Besides the
traditional electrostatic interaction, other driving forces such as
hydrogen bonding,7,8 covalent bonding,9 base-pair interactions,10
guest–host interactions11 as well as van der Waals interactions12
have been recently utilized to fabricate multilayer capsules. These
developments are invaluable because they allow a diverse range
of materials to be assembled into the capsule walls and additional
control over the structures and properties of obtained capsules.13
Therefore, by using this technique capsules with well-controlled
size and shape, finely tuned wall thickness and variable wall
compositions can be obtained.14 Furthermore, the templates
also can supply additional opportunities for the control of
capsule structures.15,16 The ability of precise manipulation of
capsule structures enables the tailoring of permeability,17
loading and release,18–21 mechanical properties22,23 as well as
biofunctionalities24 of the capsules.
At the beginning the studies on LbL multilayer capsules are
mainly focused on the fabrication and basic physicochemical
properties.14 However, the past decade has witnessed a rapid
increase of research concerning their functionalization and
applications, particularly in the biomedical fields such as drug
delivery, biosensors and bioreactors.25 Very recently, several
excellent articles have reviewed the progress of LbL capsules
as drug delivery systems,8,26–34 optical biosensors35 as well as
reactors.36,37 Another tendency in this field is the continuous
development of new fabrication strategies, which can endow
the capsules with novel structures and properties.8,38 In this
critical review, we will highlight the very recent (i.e. the last
5 years) progress of the LbL multilayer capsules. First, we will
focus on the advances in assembly of capsules by the LbL
technique, emphasizing on tailoring the properties of hydrogen-
bonded multilayer capsules by cross-linking, and fabrication of
the capsules based on covalent bonding and bio-specific inter-
actions. Then we overview the fabrication strategies that can speed
up and scale up capsule fabrication. In the following sections,
we will introduce the multi-compartmental capsules and the
capsules that can transform their shape under stimulus. Finally,
we will describe the biomedical applications of LbL capsules, with
special emphasis on drug carriers, biosensors and bioreactors.
2. Advances in assembly of multilayer capsules by
the LbL technique
2.1 Cross-linking to tailor the properties of hydrogen-bonded
multilayer capsules
Cross-linking is an effective way to enhance the stability and
tune the properties of multilayer capsules. Even for the multi-
layer capsules assembled through electrostatic interaction, in
some cases cross-linking is still necessary for the capsules to
survive through harsh conditions such as high ionic strength,
extreme pH and strong polar organic solvent.39–43 Moreover,
cross-linking can effectively manipulate the permeability and
mechanical strength of capsules.39,42,43 The LbL assembly of
multilayers through hydrogen bonding has been extensively
developed.7,8,13 However, further stabilization is required for
biomedical applications since most of these multilayers will be
disassembled under physiological conditions.44,45 The first cross-
linking method is carbodiimide chemistry.46–48 Uncross-linked
components can be selectively released at higher pH, yielding
single component and hydrogel-like microcapsules.49,50 These
capsules exhibit reversible pH-responsive swelling and shrinking,
which can be used for loading and releasing macromolecules.
Fig. 1 Schematic illustration of the polyelectrolyte deposition process
and of subsequent core decomposition resulting in hollow capsules.
Reprinted with permission from ref. 6. Copyright 1998, Wiley-VCH.
Fig. 2 PMASH–PVPON capsule wall (a) under LbL polymer deposition
conditions, (b) cross-linked at physiological pH, and (c) under cellular
reducing conditions. Reprinted with permission from ref. 53. Copyright
2009, American Chemical Society.
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One of the significant advances in this issue is the revisable
stabilization of hydrogen-bonded LbL capsules via disulfide
bonds.8,51 In this strategy, the key step is to modify at least one
of the components, for example, poly(methacrylic acid) with
thiols (PMASH), which can be further cross-linked under
oxidative conditions to stabilize the capsule wall. The
uncross-linked component poly(vinylpyrrolidone) (PVPON)
can be selectively removed, yielding stable single component
hydrogel capsules. Under reductive conditions, such as inside
cells, the disulfide linkages can be cleaved by glutathione,
resulting in disassembly of the capsules (Fig. 2). Subsequently,
the influences of thiol content, molecular weight of PVPON,
oxidation reagents, cross-linking way as well as layer number
on the properties of capsules such as degradation rate, perme-
ability and cargo retention are systematically investigated.52–55
The obtained knowledge can be used to optimize the prepara-
tion conditions and precisely control the properties of the
capsules, highlighting the virtues for encapsulation and delivery
of diverse therapeutic substances.56–58
Click chemistry with the features of high efficiency and
selectivity under mild conditions is another powerful tool
for cross-linking of the hydrogen-bonded multilayers and
microcapsules.59–65 In a general strategy, one component is first
modified with alkyne moieties and then alternately assembled
with another component on silica particles via hydrogen-
bonding. The films are cross-linked with a bisazide linker,
followed by removal of the template and uncross-linked
component at physiological pH through hydrogen bonds
disruption, yielding single-component hydrogel capsules
(Fig. 3). By choosing different alkyne-modified polymers,
bisazide linkers as well as the multilayer assembly sequence,
the properties of the capsules can be well manipulated. For
example, assembly of alkyne-modified PVPON (PVPONALK) and
poly(ethylene glycol) (PEG) results in low-fouling capsules60,62
while combination of pH sensitive alkyne-modified polymers
and reduction-sensitive bisazide linkers yields dual-responsive
capsules.65
2.2 Capsules directly assembled by covalent bonding
Zhang et al. first fabricated the covalent LbL microcapsules
through the reaction of N-methyl-2-nitro-diphenylamine-
4-diazoresin (NDR) and m-methylphenolformaldehyde resin
(MPR) in methanol.9 Similarly, microcapsules with a high
modulus and stability are fabricated through a coupling
reaction between epoxides and amines in organic solvent.66
The obtained capsules are very stable against harsh conditions
due to the covalent structure.9,66 More importantly, assembly
in organic solvents greatly expands the range of materials
adopted by the LbL technique. The reaction between amine
and aldehyde is fast and efficient in aqueous solution at room
temperature, and thereby is suitable for the covalent LbL
Fig. 3 LbL assembly of low-fouling PVPONAlk capsules covalently cross-linked by click chemistry. Hydrogen-bonded multilayers of PMA and
PVPONAlk are assembled onto colloidal silica templates precoated with a layer of PVPON. Free alkyne groups are then used to covalently cross-
link the PVPONAlk in the multilayer by click chemistry with a bisazide linker containing a disulfide bond. After removal of the template particle
and subsequent release of PMA at pH 7, low-biofouling PVPON capsules that can be degraded in reducing environments are obtained. Reprinted
with permission from ref. 60. Copyright 2009, American Chemical Society.
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assembly in aqueous solution. Using this feature, single poly-
electrolyte (PE) component multilayers and microcapsules are
fabricated through glutaraldehyde (GA)-mediated covalent
assembly.67,68 This method can be extended to other biomacro-
molecules such as polysaccharides, polypeptides, and proteins.69
However, the main drawback of the above-mentioned methods is
that the obtained capsules may largely lose their stimuli-responsive
properties due to the uncontrollable covalent reactions.67,68 One
solution to this problem is to carefully control the content of
reactive groups in polymer chains, leading to a controllable
reaction degree and a number of functional groups. This concept
was first demonstrated by Such et al.70 Poly(acrylic acid) (PAA)
molecules grafted with minor amounts of either alkyne
(PAA–Alk) or azide (PAA–Az) are alternately assembled on
silica particles through the click reaction, yielding hollow micro-
capsules after core removal. Due to the carboxylic acid groups in
PAA, the capsules show reversible swelling and shrinking by up
to 70% in response to acid–base pH cycling. A detailed study is
further performed to investigate the influences of assembly
conditions such as pH, ionic strength as well as grafting degree
of PAA on the structures and properties of the obtained films
and capsules.71 Through this method, degradable microcapsules
also can be produced using dextrans modified with alkyne and
azide groups through hydrolysable carbonate esters.72,73
As a natural protein, bovine serum albumin (BSA) is con-
sidered to be biocompatible and biodegradable. It has a defined
structure with high content of charged residues of amino acids,
such as aspartic and glutamic acids, lysine, and arginine.74,75
GA only cross-links the amine group of lysine,76 while the other
charged residues of amino acids still exist. Consequently,
pH response of the resultant products can be expected.
Moreover, the GA cross-linked albumin microspheres are
relatively non-immunogenic and biodegradable in muscle without
adverse tissue reactions.77 Therefore, the GA cross-linked
BSA spheres/capsules are promising for pharmaceutical
applications. In a recent study,78 BSA was first assembled on
the surface of colloidal particles, which were then suspended in
GA solution to cross-link the adsorbed BSA layer and activate
the surface for next covalent assembly of BSA. This procedure
is repeated several times until the desired layer number is
reached. Hollow capsules are obtained by removal of the cores.
The capsules show reversible pH-controlled permeability, which
can be used to encapsulate macromolecules.
Recently, Jia et al.79 introduced biocompatible, biodegradable,
stable and nontoxic polysaccharide-based microcapsules, which
were fabricated by covalent LbL assembly of chitosan (CS) and
alginate dialdehyde (ADA) through amine and aldehyde reac-
tion. In this strategy, polysaccharides such as alginate, heparin as
well as starch can be modified with aldehyde groups which can
react with the amine groups in CS. However, electrostatic
interaction may also contribute to the multilayer assembly in
the CS–ADA system. Interestingly, the prepared (CS–ADA)5/CS
microcapsules display intriguing autofluorescence without any
external fluorochromes. This phenomenon resulted from the
n–p* transition of the CQN bonds in the Schiff base formed
between amino and aldehyde groups.80–82 These autofluorescent
microcapsules can avoid external fluorochromes used in bio-
logical tracing, showing great promise in biomedical applications.
In the following work of the same group,83 low-molecular-weight
and redox-responsive cystamine dihydrochloride (CM) is
assembled with ADA to fabricate microcapsules, which exhibit
pH- and redox-responsive as well as autofluorescence (Fig. 4).
2.3 Capsules assembled through bio-specific interactions
The specific interactions between complementary DNA bases
are stable enough under physiological conditions in nature.
Therefore, the biocompatible and biodegradable DNA is very
Fig. 4 (a) LbL assembly of autofluorescent polysaccharide-based microcapsules uploading docetaxel (Dtxl) against tumor cell proliferation. The
formulated Schiff base and disulfide bonds form capsules with pH- and redox-responsive properties for pinpointed intracellular delivery based on
physiological difference between intracellular and extracellular environments. The as-obtained microcapsules could be degraded into ADA and
mercaptoethylamine (MEA). (b) Typical CLSM images of the microcapsules excited at 405 nm and collected 500–550 nm (green). (c) Fluorescence emission
spectrum of the selected region in the CLSM image of (ADA–CM)5 capsules. Adapted with permission from ref. 83. Copyright 2012, Wiley-VCH.
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attractive if it can be prepared into multilayer films and
capsules. This was first demonstrated by the Caruso group,10
and the factors governing the structures and properties of the
films and capsules were systematically investigated.84–89 It is
necessary for the pre-adsorbed DNA to be available for the
subsequent layer to hybridize, thus the oligonucleotides with
multiple nucleotide units are needed.84 Furthermore, the
oligonucleotide length plays an important role, and at least
10 bases per hybridizing block in the DNA diblocks are
required for successful multilayer film formation. Also the
stability and melting temperature of the films increase along
with the increase in oligonucleotide length.86,88 The use of salt
in forming DNA multilayers is crucial in promoting and
maintaining hybridization of complementary base pairs by
screening the repulsive forces between the negatively charged
DNA main chains.89 The obtained DNA capsules shrink after
template removal,85 and the shrinkage can be greatly inhibited
by hybridizing additional oligonucleotide sequences that can
crosslink the films.90 Since modern biotechnologies enable the
precise control over the sequences of DNA, the properties of
consequent DNA films and capsules can be well tailored. For
example, capsules assembled from a DNA with restriction-
enzyme cut sites can be only degraded in the presence of a
specific enzyme.91 These results are important for precise
control of the structures and properties of DNA films and
capsules, which have great potential applications in the fields
of sensing, diagnostics, and drug/gene delivery.
Furthermore, DNA sequences can be grafted to diverse
polymers to form DNA–polymer conjugates, which can be
further assembled into multilayer thin films. For example,
DNA-grafted poly(N-isopropylacrylamide) (PNIPAM)micelles
are assembled into multilayer thin films through specific base
pair interactions, resulting in further DNA–PNIPAM micro-
capsules with hierarchical structures.92 The G-quadruplex–
polymer conjugates also can be assembled onto a template
surface via hybridization with 30-mer cytosine strands using
the LbL approach to form microcapsules. The residual and
functional quadruplex moieties can be used to effectively bind
therapeutic agents.93
Besides the specific base pair interactions, carbohydrate–
protein interaction is another type of important bio-specific
interactions which participates in a wide variety of biological
and pathological events.94–96 These interactions are, in nature,
a combination of multiple hydrogen bonding and hydro-
phobic interactions.95 Although both of them are weak and
reversible, superior strength of the carbohydrate–protein
interactions arises from the numerous binding sites. Therefore,
novel molecular-engineered microcapsules built from these
interactions may simultaneously possess good stability and
responsiveness to external stimulus. Concanavalin A (Con A),
a well-investigated lectin derived from Jack beans, is known to
possess specific binding capacity to glucose, mannose, fructose
and their corresponding polysaccharides such as dextran and
glycogen.97–99 Thus, Con A can form complex with dextran
and be employed to fabricate thin films with glycogen through
lectin–carbohydrate interactions.100–102 These structures show
readily their responses to glucose.99,102 Hence, it is expected
that the hollow capsules fabricated by Con A and glycogen in
the LbL manner remain stable at the physiological pH range
due to the relatively strong multiple hydrogen bonding but
readily respond to glucose due to its competitive-binding with
Con A. This concept has been realized recently and is further
used to create multi-compartmental micelles-loaded micro-carriers
(Fig. 5).103 The sequential multilayer film growth proceeds success-
fully on both planar and curved substrates when the Con A
molecules adopt confirmation of tetramers or more complicated
aggregates. The obtained capsules show layer-number-dependent
shell shrinkage, distortion and densification. Particularly, when
the layer number is smaller than 7, the capsules shrink to different
extents but their wall thickness remain approximately unchanged,
suggesting molecular rearrangement during the template removal
process. The capsules are stable in a medium of pH 6–9 and
survive through 3 M urea treatment for at least 1 h, indicating
good capsule stabilities. These capsules show specific responses to
glucose, mannose, fructose and dextran but not to lactose and
galactose due to the mismatch structure. The responses of these
assemblies to carbohydrates are independent of the external pH
value in the range 6–9. Triggered by these stimuli, polymeric
micelles pre-loaded in the capsules can be released. With the
carbohydrate-responsive properties in the physiological pH range
as well as the possibility of incorporation and subsequent release
of functional nano-objects, these smart capsules are expected
to find important applications in the fields of drug delivery,
bio-sensing as well as bio-reactions.
3. Speed-up the capsule fabrication by LbL-derived
methods
Using the LbL technique, the multilayer capsules with well-
controlled size and shape, finely tuned capsule wall thickness
and compositions, tailored functionalities can be successfully
fabricated. Despite all the attractive advantages, the main
drawbacks of the LbL technique are the tedious and time-
consuming fabrication process and the waste of materials.
Therefore, development of other facile methods with great
Fig. 5 (a) Schematic illustration of the structure of the Con A–glycogen
smart capsule and its response to carbohydrates. Fluorescent images
of Con A–glycogen microcapsules before (b) and after treatments with
(c) 10 mg ml�1 glucose for 20 s. Adapted from ref. 103.
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ease of fabrication and eventually scalable production of
capsules is of both scientific and technical importance. In the
following sections, we will introduce several methods which
may speed up and scale up the capsule fabrication. Most of these
methods are directly derived or inspired by the LbL methods.
3.1 Controlled precipitation (CP)
The CP method can deposit a thick enough layer on a template
surface. For example, PEs,104 nanoparticles (NPs)105 as well as
dextran106 can be precipitated on a template surface in a controll-
able way by gradual change of the solvent quality. Obviously, the
hollow capsules only can be obtained if the shell can survive core
removal, thus stabilization of the shell is often needed, as reported
recently for the BSA mono-component microcapsules.107,108
Desolvation of BSA from its aqueous solution is achieved by
dropwise addition of poor solvent, e.g. ethanol. The desolvated
BSA molecules are captured by MnCO3 microparticles to form a
continuous thin film on the surfaces. After cross-linking of the
films and core removal, hollow and intact microcapsules are
obtained with well dispersion in aqueous solution. In another
case, if the precipitation is induced by specific interactions of two
substances in the same aqueous solution, the formed film on the
template particle will be stable enough in solution and no further
cross-linking is needed. This one-step CP process is demonstrated
by fabrication of Con A and glycogen complex capsules.109 The
shells are formed on polyethyleneimine (PEI)-modified carbonate
particles by dropwise addition of Con A solution into glycogen
solution, resulting in stable hollow capsules in aqueous solution
after core removal. These capsules retain the responsiveness to
glucose and glucose-containing polysaccharides such as dextran.
Employing micelles-adsorbed CaCO3 particles as the templates,
the micelles also can be incorporated into the capsules. These
multi-compartmental carriers still can be destroyed by glucose,
providing the possibility to load and release multiple reagents.
In the above-mentioned CP methods, precipitation of the
wall materials must be induced by addition of external sub-
stances. Very recently, a core-mediated precipitation method is
developed to fabricate CS microcapsules with micron-size wall
and onion-like concentric layered structures.110 The partial
dissolution of CaCO3 particles in a slightly acidic CS solution
induces pH increase, and thereby precipitation of CS on the
templates. Repeat of this process results in CS capsules with an
onion-like concentric layered structure (Fig. 6). The capsules
are stable without cross-linking and can be well dispersed in
aqueous solutions. This pH increase is automatically realized
and self-restricted by the partial dissolution of CaCO3 cores,
and no deliberate adjustment of the pH value is required.
3.2 Core-mediated in situ PE coacervation
Previously we fabricated multilayer microcapsules using
poly(styrene sulfonate) (PSS)-doped CaCO3 particles as
templates.111,112 After core removal, part of the initially doped
PSS molecules in the CaCO3 particles are encapsulated within the
microcapsules and intertwined with the multilayers, enabling the
capsules to effectively sieve charged molecules. A model is sug-
gested to depict the topology of the microcapsules: with a special
complex layer of poly(allylamine hydrochloride) (PAH) and PSS
(B40 nm) under the regular PAH–PSSmultilayer shell (B15 nm).
The question then arises: is it possible to obtain the intact
complex shell only? Clarification of this question is not only
helpful to confirm the deduced model but also may provide a
new simple way to fabricate hollow capsules. By assembling
only one layer of PAH onto PSS-doped CaCO3 microparticles,
followed by dissolution of the CaCO3 particles with disodium
ethylene diamine tetraacetate dihydrate (EDTA), capsules are
obtained via in situ complexation of the oppositely charged
PEs when they encounter during core removal.113 The capsules
have a size of 150% of their templates due to the osmotic-
induced expansion114,115 and plasticity of the primary shells
during core removal. Due to the less regular internal structure
and cross-linking degree, elasticity modulus of the complex
capsule (140MPa) measured by an osmotic pressure method116,117
is only half of their regularly assembled multilayer counterpart.
This drawback can be remedied by GA cross-linking under mild
conditions.118 Moreover, if the adsorbed PAH layer is cross-
linked followed by core removal in a solution of EDTA mixed
with PAH, microcapsules with charge-controlled permeability
can be fabricated by such an in situ coacervation method
(Fig. 7).119 This new technique has the advantages of time and
materials saving, and can be easily scaled-up.
3.3 Polymerization on the surfaces of templates
Polymerization on a sacrificial particle surface is another
method for the speed-up and scale-up fabrication of hollow
capsules. Template polymerization has been proven a useful
method to obtain multi-component materials.120–122 In this
technique, a polymer is used as the template to associate with
monomers by hydrogen bonding, electrostatic force, or other
interactions, followed by polymerization of the monomers in
which propagation of a radical occurs along the template
polymer chain during most of its lifetime. Radical template
polymerization can yield polymer–polymer complexes held by
cooperative interactions of complementary macromolecules.
This method has been applied to forming ultrathin layers on
colloidal particles and further to fabricating hollow capsules either
driven by electrostatic interaction123 or hydrogen bonding.124
Fig. 6 (a) Schematic illustration of the formation process of chitosan
(CS) microcapsules with a micron-size thick wall and onion-like
structure via a core-mediated precipitation method. CLSM image of
microcapsules with 1 (b) and 4 (c) precipitated CS layers. The red and
green layers are tetramethyl rhodamine isothiocyanate (TRITC) and
fluorescein isothiocyanate (FITC) labeled CS, respectively. Adapted
from ref. 110.
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Poly(vinylpyrrolidone) (PVP) and silica particles are adopted
as the molecular template and sacrificing template, respectively.
The silica particles are modified by 3-(trimethoxysilyl)propyl
methacrylate (MPS) to introduce polymerizable CQC bonds.
Then acrylic acid (AA) and PVP are added in the suspension
and the pH is adjusted toB3. The PVP molecules can not only
stabilize the particle suspension but also act as the molecular
template to bind AA monomers through hydrogen bonding.
The PVP–AA complex is subsequently transformed into the
PVP–PAA complex through polymerization. Consequently, the
initially adsorbed PVP–AA conjugates on the particle surfaces
form the original shells, which become thicker and thicker along
with the polymerization proceeding. This is mainly driven by
the ‘‘grafting from’’ mechanism (i.e. radicals in the shells initiate
polymerization of AAmonomers associated with PVP) and also
possibly by the ‘‘grafting to’’ mechanism (i.e. the PVP–PAA
complexes are grafted to the shells by radial coupling termination).
Nevertheless, hollow capsules composed of PVP and PAA
complexes are obtained after etching out the templates. The
wall of the capsule can be further cross-linked, which endows
the microcapsules with better stability against large pH
fluctuations and reversible swelling–shrinking property at high
and low pH values, respectively.
More recently125,126 a strategy has been proposed to fabricate
polydopamine (PDA) capsules through the oxidative polymeri-
zation of dopamine and the spontaneous deposition of PDA on
the template surface, followed by template removal (Fig. 8).
This process only involves a single-step thin film assembly, but
the wall thickness can be well controlled by the polymerization
time125 and cycles126 in a nanometer scale. This method is very
elegant and versatile because the oxidative polymerization of
dopamine takes place under very mild conditions (slightly
alkaline aqueous solution and room temperature) without any
initiator, and PDA can spontaneously deposit virtually on any
surface.127,128 For example, PDA is successfully deposited on
dimethyldiethoxysilane (DMDES) emulsion droplets with a size
Fig. 7 (a) Schematic illustration to show the fabrication process of the in situ coacervated microcapsules with filled PSS, which possess charge-
controlled permeation property. They repel negatively charged fluorescein (b) but attract positively charged rhodamine 6G (c). Adapted from
ref. 119.
Fig. 8 Assembly of a polydopamine (PDA) film onto a particle and subsequent capsule formation. Oxidative polymerization of dopamine
showing two of the possible structures formed. Reprinted with permission from ref. 125. Copyright 2009, American Chemical Society.
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ranging from 400 nm to 2.4 mm.129 The obtained capsules are
very robust due to the cross-linked structure and can be loaded
with low-molecular-weight dyes.126 These capsules composed
of single common and naturally originated compounds exhibit
negligible toxicity,125 which makes PDA capsules ideal candi-
dates for therapeutic delivery and other biomedical applica-
tions. Moreover, dopamine can be used to modify biopolymers
and mediate assembly of biodegradable microcapsules through
its oxidative polymerization too,130 which greatly extends the
application fields of this method.
3.4 Infiltration and cross-linking on porous templates
Besides deposition on the surface of sacrificial templates, the
materials also can infiltrate into the pores of porous templates.
After stabilizing by cross-linking, capsules or spheres can be
obtained. Indeed, porous CaCO3 and SiO2 microparticles have
been used as templates to fabricate microcapsules with PE
complexes inside for biomacromolecule encapsulation.131,132
By simply mixing the capsules and biomacromolecules aqueous
solution, enzymes and proteins are loaded with high efficiency.
For example, by using porous CaCO3 particles multilayer
capsules with a cell-like topology are successfully fabricated.
They are able to spontaneously load various substances in
aqueous and ethanol solutions.133 Fabrication of such a kind
of capsules relies on infiltration of PEs into the pores of the
template to form PE complexes. Alternatively, SiO2 particles
with a solid core (ca. 300 nm) and a mesoporous shell (ca. 60 nm)
are employed as templates too. Macromolecules are infiltrated
into the mesoporous shell by solution adsorption, followed by
covalent cross-linking. Polymeric capsules are obtained after
template removal (Fig. 9).134 This method has significant advan-
tages compared with the previous one. First, formation of
capsules only needs a single macromolecule infiltration step
which makes the fabrication process speed up. Second, in
principle any macromolecule and its corresponding cross-linking
agent which can infiltrate into the pores can be used to fabricate
such capsules (Fig. 10). This advantage makes the method very
powerful for tailoring the properties of capsules. Finally, the
thickness and porosity of the capsule wall can be controlled by
the features of the porous silica shell. In another very recent
work of the same group,135 bacterially synthesized cysteine-
functionalized poly(L-glutamic acid) (PGA) molecules with
variable percentages of cysteine (6–30%) were infiltrated into
and cross-linked. After core removal, single-component porous
peptide microparticles are obtained. The position of the cross-
linking group (cysteine), which can be precisely tuned by the
bioengineering method, has a great impact on the degradation
rate of the assembled carriers. Thus, this method provides new
opportunities for designing delivery systems with a controlled
degradation property and drug release rate.
4. Capsules with subcompartments
The creation of advanced, multi-compartmental micro- and
nanostructures has received tremendous attention in the past
decades due to their ability to load and release multiple reagents
and applications in various fields.136–139 Hollow capsules with sub-
compartments are of extreme interest since they possess a large
inner space separated from the environment and resemble the
structure of cells. Compared with those traditional methods the
LbL technique is much powerful to design highly sophisticated
capsules. By integration of other techniques, so far many types of
capsules with different subcompartments have been fabricated.38
There are two ways to incorporate the sub-compartments, i.e.wall
decoration and interior loading.
Fig. 9 Schematic representation of the preparation of single-component
macromolecular capsules by using solid core and mesoporous shell
(SC–MS) silica particles as templates. Reprinted with permission from
ref. 134. Copyright 2008, American Chemical Society.
Fig. 10 Poly(L-lysine) (PLL) (a and b) and poly(L-glutamic acid)
(PGA) conjugated with doxorubicin (DOX), and (c and d) nanocapsules
formed using SC–MS templates. The cross-linking agents used are GA
(a), dimethyl 3,30-dithiopropionimidate dihydrochloride (DMDTPC)
(b), and cystamine (c and d), respectively. Panels a–c are TEM images,
the insets of panels (a and c) are SEM images, and panel (d) is a
fluorescence microscopy image of the nanocapsules whose fluorescence
signal arises from encapsulated DOX. Reprinted with permission from
ref. 134. Copyright 2008, American Chemical Society.
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Kreft et al. first reported the LbL microcapsules with a shell-
in-shell structure for integrated and spatially confined enzymatic
reactions.140 Spherical ball-in-ball particles consist of two
concentric CaCO3 compartments, which are separated by PE
multilayers and independently loaded with enzymes. By
assembly of multilayers on such templates followed by CaCO3
removal, the obtained shell-in-shell microcapsules contain
enzymes and are separated by semipermeable membranes.
They can mediate coupling bis-enzymatic reactions. Besides
the above-mentioned concentric structure, other complicated
structures such as pericentric, innercentric and acentric ones
can be obtained as well.141,142
De Geest et al. reported the assembly of multilayers on big
hydrogel particles (hundreds of microns) in which tens of
hollow LbL microcapsules or microparticles are loaded.138,143
Upon degradation of the hydrogel particles, the inside osmotic
pressure will increase and may eventually become large enough
to break the multilayers, leading to capsule rupture and thereby
release of the encapsulated subcompartments.
Recently, the Caruso group reported the incorporation of
intact liposomes into LbL capsule walls or inside capsules to
prepare ‘‘capsosomes’’, which can be then employed as enzymatic
reactors and delivery vehicles for hydrophobic cargos.144–148
Cubic mesophase lipid NPs also can be incorporated into capsule
walls through a similar strategy.149 For sure this kind of
‘‘capsosomes’’ is a promising new concept toward the design
of artificial cells in which complicated enzymatic reactions are
performed.150,151
Alternatively, polymeric micelles also can be incorporated
into the walls or interiors of LbL capsules as the subcompart-
ments. The micelles possess advantages of sustained release of
hydrophobic substances. In particular, polymeric micelles
possess a unique core–shell structure and relatively good
stability,152and thereby have found tremendous applications
as drug-delivery vehicles,153 nano-reactors154 and bio-sensors.155
Hence, the micelles-incorporated microcapsules maintain the
advantages of both micro- and nano-structures. Hollow micro-
capsules containing polymeric micelles in their walls are fabri-
cated by alternating assembly of PAH and poly(styrene-b-acrylic
acid) (PS-b-PAA) micelles on MnCO3 microparticles, followed
by removal of the templates in acid solution.156 Due to the high
stability in aqueous solution, the PS-b-PAA micelles retain their
structure during the whole assembly process. It is unexpected,
however, that the as-prepared microcapsules show extra-
ordinary stability against concentrated HCl (37%) and 0.1 M
NaOH solutions. No variation in capsule size or shape is
observed in acidic solution, while slight swelling and distortion
of the capsules takes place in alkaline solution. However, these
capsules completely recover their original size and morphology
after being incubated in acidic solution again. This extraordinary
stability against highly acidic or alkaline conditions is possibly
due to the hydrophobic interaction between PS cores of the
micelles as well as hydrogen bonding of the PAA chains in
adjacent layers and PAH chains. The capsules obtained can serve
as models for multi-compartmental containers which may
encapsulate both hydrophobic and hydrophilic substances. The
extreme stability of the capsules against harsh conditions in an
aqueous environment can greatly broaden their potential
applications, while their responsiveness to external stimuli
turns out at high pH. It might also be possible to tailor the
release of substances in each compartment by proper molecular
design of the micelles and incorporation of various functional
components.
The incorporation of polymeric micelles into LbL capsule
interiors has been presented by Li et al.157 as well as Tong
et al.158 In the latter method,158 LbL assembly is conducted on
CaCO3 microparticles pre-doped with PS-b-PAA micelles,
resulting in encapsulation of micelles after core removal.
Distribution of the micelles in templates and capsules is char-
acterized by transmission electron microscopy and confocal laser
scanning microscopy (CLSM). The micelles inside the capsules
connect with each other to form a chain and network-like
structure with a higher density near the capsule walls. The
hydrophobic multiple compartments can serve as reservoirs for
loading of hydrophobic drugs such as triclosan, while the
negatively charged PAA corona of the micelles are able to
induce spontaneous deposition159–163 of water-soluble and posi-
tively charged drugs such as doxorubicin (DOX). The concen-
trations of hydrophobic and water-soluble drugs are found to be
3 and 28-fold of the feeding values, respectively. Therefore,
capsules with this synergetic feature show their great promise
in loading of drugs with different physicochemical properties.
Furthermore, the wall of such multi-compartmental capsules
also can be engineered to be responsive to external stimuli. Among
various types of external stimuli such as pH,164 temperature165
or laser,166 glucose is a promising candidate for in vivo appli-
cations since it is abundant in human blood. Incorporation of
sub-compartments such as micelles into the glucose-responsive
vehicles results in smart multi-compartmental carriers and
further micelles release under glucose treatment.103
5. Shape transformation of capsules
The smart capsule systems are of high attraction due to their
ability to respond to the alteration of environment conditions.
LbL assembled capsules can change their structure and properties
intelligently in response to various stimuli such as pH,11,40,164,167–171
ionic strength,172–176 temperature,165,173,177–179 light,166,180–184
and redox potential.185 Most of the intelligence of the hollow
structures, however, results from controllable swelling and
shrinking, accompanying with permeability change.186 Less
concern is paid to shape transformation of the hollow structures,
which is only observed in vesicles and hollow silica spheres
previously.187–193 For instance, budded hollow silica spheres
can be constructed by kinetic self-assembly of silica precursors
and continuously budding surfactants,187 while block copoly-
mers can form vesicles of a special morphology with protruding
rods or porous spheres by changing polymer concentration and
solvent property.188–190 More interestingly, vesicles made of
giant hyperbranched polymers exhibit shape transformation
analogous to cellular processes such as birth, budding, fusion,
and fission.191–193 Therefore, not only the transformation
process of the hollow structures but also the underlying physico-
chemical mechanisms, which may give a hint on the biological
and natural processes, are of high interest.194
Recently, single-component microcapsules have been fabri-
cated in our group by an in situ reaction of reactive hydro-
phobic low-molecular-weight molecules with the corresponding
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PE-doped CaCO3 microparticles, followed by core removal.195–196
The first example is the capsules made of ferrocenecarboxaldehyde
(Fc-CHO) and PAH-doped CaCO3 microparticles.195 The
single-component microcapsules are stabilized by hydro-
phobic aggregation of Fc moieties. The microcapsules
have very thick shells, leading to a robust capsule structure
that is less collapsed in a dry state. Because of the excellent
redox properties of Fc, the PAH–Fc microcapsules show
reversible swelling and shrinking in response to oxidation
and reduction, accompanying with reversible permeability
change.
Through a similar procedure, pyrenecarboxaldehyde is
reacted with the doped PAH to fabricate PAH–pyrene (Py)
microcapsules.196 Surprisingly, one-dimensional nanotubes
(1D-NT) or nanorods (1D-NR) are protruded from the
PAH–Py microcapsules when they are incubated in pH 0
and pH 2 solutions, respectively. The 1D-NTs keep growing
with incubation time. Meanwhile, the microcapsules fade
gradually and disappear completely after 144 h (Fig. 11).
Similarly treated micelles, which are assembled from deliber-
ately synthesized PAH–Py polymers, can transform into one-
dimensional structures too, revealing the chemistry-driven
nature of the phenomenon. The one-dimensional nanotubes
consist of only 1-pyrenecarboxaldehyde with ordered p–pstacking, and exhibit a helical structure and anisotropic pro-
perty. The hydrolysis of the Schiff base and its rate at different
pH values (10 times slower at pH 0 than at pH 2) play a key
role in determining the final nanostructures. The linear PAH
directs the regular building up process especially for the
nanotubes. Using this unique feature, hollow capsules budded
with nanotubes or nanorods mimicking the cellular protrusion
of filopodia are successfully prepared when the process is
terminated at an appropriate time (Fig. 11). These results
and the proposed mechanism open new opportunities for
design of novel materials for nanoscience, and biological and
other advanced technologies.
Attempt is then made to control the 1D-NR growth state
from the PAH–Py microcapsules by chemical cross-linking
and surface modification. After GA cross-linking, the micro-
capsules can keep stable even after protrusion of the 1D-NRs.
Hence, the protruded 1D-NRs on the capsule surface are
easily tuned in terms of length and coverage rate by control-
ling the pH value of the incubation solution. For instance, the
1D-NRs are very short at pH 2 with a very high coverage rate;
however, at pH 1 the 1D-NRs grow longer but the coverage
rate becomes smaller. Because of the reversible reactive pro-
perty of the Schiff base, the 1D-NRs can be removed and
re-protruded from the capsules in a cycling manner.
The 1D-NRs also can grow in the LbL assembled capsules
in a controllable manner (Fig. 12).197 For this purpose,
PSS–PAH multilayers are assembled on the surface of CaCO3
(PAH–Py) microparticles, yielding PAH–Py and (PSS–PAH)ndouble-shell capsules. By incubation of the obtained capsules
in pH 2 solution, the 1D-NRs grow within the (PSS–PAH)nmultilayer capsules in three dimension. Their encapsulation
rate is controlled by the layer number and the size of the
(PSS–PAH)n capsules. Finally, the (PSS–PAH)n capsules can
be destroyed by ultrasonication to release the 1D-NRs, which
have exactly the same chemical and fluorescent properties as
their counterpart fabricated in solution. The fluorescence
emission intensity of Py NRs inside the capsules can be tuned
by a charge transfer pair. This novel composite structure with
PAH–Py NRs inside PE multilayer microcapsules provides a
creative strategy for in situ nanomaterials fabrication, illumi-
nating the trend for controllable properties and functions of
smart nanodevices.
Inspired by the above finding, PAH–Py NRs consisting of a
Py–CHO core and a PAH shell are successfully prepared by
surface grafting of PAH onto Py–CHO NRs.198 The Schiff
base reaction between Py–CHO and PAH on the interface of
NRs and solution results in a more curved and flexible
structure as a result of partial loss of Py–CHO from the NRs.
Fig. 11 TEM images showing the process of nanotube protruding from the PAH–Py microcapsules incubated in pH 0 HCl for 0, 24, 48, 96, and
144 h, respectively. (f) Optical images (inset, a higher magnification) showing the protruded nanotubes from the PAH–Py microcapsules incubated
in pH 0 HCl for 30 h. SEM images of a microcapsule with nanotubes after treatment in pH 0 HCl for (g) 30 h and (h) 72 h, respectively. (i) SEM
image of a microcapsule with nanorods after treatment in pH 2 HCl for 1 h. Reprinted with permission from ref. 196. Copyright 2011, American
Chemical Society.
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The hydrophobic Py–CHO NRs are easily precipitated in
water. In sharp contrast, the PAH–Py NRs with a hydrophilic
and charged PAH layer can be suspended stably in water for at
least 3 months. Because of the charge attraction and coordina-
tion effect of amino groups, AuNPs can be either adsorbed or
in situ synthesized on the PAH–Py NRs surface. It is worth
mentioning that the initial fluorescence emission of Py largely
remained due to the excellent isolation effect of PAH, which
avoids direct contact between Py and the Au NPs. Using a
similar process, other hybrid organic–inorganic functional
nanomaterials with controlled physical and chemical struc-
tures can be synthesized. Therefore, this new approach can
effectively modify organic surfaces with NPs, endowing them
with multiple functions.
6. Biomedical applications
6.1 Drug carriers
The unique colloidal structure of LbL assembled capsules
offers a very versatile platform for encapsulation, storage
and delivery of diverse substances, since those established
techniques form a powerful toolbox to effectively and precisely
control or even tailor their permeability, stimuli-responsiveness
as well as multifunctionalities. These features make the LbL
assembled capsules ideal advanced carriers for delivery diverse
drugs and biotherapeutics, as summarized in the recently
published reviews.8,21,27–29,31,33,34,199,200 Especially, experts in
this field have contributed a theme issue on ‘‘Layer-by-
Layer Self-assembled Nanoshells for Drug Delivery’’ in
Adv. Drug Delivery Rev.201 Many important issues such as
fabrication,202 encapsulation and delivery of diverse drugs and
biotherapeutics,203–205 stimuli-responsive properties,206,207
remote control,208 imaging209 as well as targeting of cancer
cells210 have been comprehensively discussed, which shall not
be repeated in this article. The following sections will focus
only on the very recent progress which is important but less
touched previously.
6.1.1 New encapsulation techniques. Many applications of
the multilayer capsules must face a challenge of efficient
loading of the desired substances, as extensively discussed in
previous review papers.19,25,29,34 This is particularly difficult
for loading of low-molecular-weight and water-soluble species,
which can freely diffuse through the semipermeable walls in
aqueous solutions.211 Small molecules can be encapsulated by
preferred precipitation inside the capsules due to the differences
of physicochemical properties such as pH and solvent polarity
across the capsule wall.212–214 Another versatile and effective
strategy is to preload the hollow capsules with materials which
have high affinity with the substances of interest. This is initially
driven by an unexpected interesting phenomenon that positively
charged molecules can largely deposit into microcapsules
templated on melamine formaldehyde (MF) particles (the
so-called ‘‘spontaneous deposition’’ effect).159 The driving
force for the encapsulation is the existence of a negatively
charged complex PSS–MF within the capsule interior.159
Inspired by this finding, PSS-doped CaCO3 particles are
prepared and used as templates for fabrication of PSS-loaded
capsules,111 which show an intriguing ‘‘charge-controlled
attraction and repulsion’’ effect.111,112 The positively charged
and water soluble substances are automatically and very
effectively loaded into the preformed capsules.163,215 Apparent
concentration of the loaded drugs is up to hundred times of
the bulk.161,162 Nonetheless, challenge still remained to seal the
drugs inside the capsules and then control their release profile
although the strong drug–PE interaction prevents undesired
release to some extent. Kohler et al. demonstrated that
poly(diallyldimethylammonium chloride) (PDADMAC)–PSS
capsules with PSS as the outmost layer can shrink dramatically
at elevated temperature.178,179 The capsule wall becomes
simultaneously thicker and denser, resulting in dextran
Fig. 12 (A) Fabrication of PAH–Py–(PSS–PAH)n double-shell microcapsule (MC) and Py–CHO NRs formation inside the (PSS–PAH)n MC.
(B) The chemical structure of Py–CHO, PAH, and PAH–Py, and the Schiff base formation and hydrolysis. (C) CLSM images of the (PSS–PAH)12MCs containing Py–CHO NRs. Adapted from ref. 197.
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(Mw from 10 kDa to 70 kDa) encapsulation with a slightly
higher concentration than the feeding value.194 The loading of
water-soluble small molecular drugs also can be achieved
using this method.216 In our recent work,217 spontaneous
deposition and heat-induced shrinkage were integrated to
fabricate a drug carrier system, showing a high drug loading
efficiency and more controllable release profile (Fig. 13). The
PDADMAC–PSS capsules are assembled by using PSS-doped
CaCO3 microparticles as templates, so that the resultant
capsules are simultaneously loaded with PSS. While shrinkage
does occur upon heat-treatment, high efficient loading of DOX
is also facilely achieved by a simple incubation. The ratio of
interior drug concentration to that in the bulk of capsules
incubated in 0.5 mg ml�1 DOX solution is as high as 1000. The
heat-treatment does not influence obviously the drug encap-
sulation, whereas the release profiles can be effectively tuned.
Mak et al. recently demonstrated a new method named
matrix-assisted colloidosome reverse-phase LbL which can
encapsulate biomacromolecules in hydrogel microcapsules with
extremely high efficiency and retention stability.218 This method
involves two key steps: preparation of stable biomacromolecules-
loaded hydrogel microbeads (the matrix-assisted colloidosome)
using microparticles as surface stabilizers, which can be dispersed
in organic solvents; and assembly of multilayers on the
microbeads in organic solvents using nonionized PEs by the
LbL method, which prevent diffusion of the highly water-
soluble biomolecules. The encapsulation efficiency of this
method is almost 100% and even after 7 days incubation in
water the retention of encapsulated proteins is still nearly
100%. This method is a valuable addition to the family of
encapsulation techniques through the LbL approach and can
significantly contribute to the fields of bioreactors and biosensors.
In the following work of the same group, encapsulation of
biomacromolecules within microcapsules encoded with a
color/thickness scheme is further demonstrated via a similar
method. The encapsulation and encoding can be simulta-
neously achieved through an inward buildup of concentric
colored layers to create a multicolor layered polymeric shell.219
6.1.2 LbL assembly on smaller particles. Most of the LbL
capsules have a diameter of a few micrometers, which are too
large for intravenous injection. One possible solution is to
assemble multilayers on particles with a smaller size. De Koker
et al. have reviewed the progress of LbL assembly on ultra-
small (sub-100 nm) particles, which are mainly gold NPs.34
The following section shall summarize important examples of pre-
paration of stable nanocolloidal suspensions or surface modifica-
tion of polymeric NPs with a size around 200–300 nm using LbL
assembly. The particles with such a size can be injected into blood
vessels and may accumulate in cancerous tissues through the well-
known enhancer permeability and retention (EPR) effect.
The Lvov group recently reported a sonication-assisted LbL
PE coating method for non- or low-water soluble drug
NPs.220–223 Two different strategies are used.222 In the top-
down approach, nanocolloids are prepared by rupturing a
big drug powder under ultrasonication and simultaneously
adsorbed with oppositely charged PEs in a sequential manner.
In the bottom-up approach the drug is first dissolved in good
solvent (ethanol or acetone), which is miscible with water.
Drug nucleation is initiated by addition of aqueous PE
solution under ultrasonication, and the formed particles are
then sequentially coated with multilayers (Fig. 14). The stable
nanocolloids with a size in the range of 60–200 nm and a very high
drug content (up to 90%) have been successfully fabricated.223
The multilayers on the nanocolloids can not only facilitate
their stable dispersion in aqueous solution but also control
Fig. 13 (a) Schematic illustration to show the high efficient loading of low-molecular-weight drugs into polyelectrolyte encapsulated multilayer
capsules through the combination of spontaneous deposition and heat-induced shrinkage. The blue layer refers to the stable complex or adsorbed
layer, which is formed by the first PDADMAC layer and liberated PSS molecules during the core removal process. The pale blue rhombus refers to
the shrunk and reorganized capsule wall. (b) SEM images of PSS–(PDADMAC–PSS)5 capsules and (c) TEM image of a ultrathin section of the
capsules after being incubated at 80 1C for 20 min. (d) CLSM image of PSS–(PDADMAC–PSS)5 capsules loaded with DOX by incubation at 80 1C
for 20 min. The inset shows the corresponding SEM image. Adapted from ref. 217.
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the sustained release pattern. This method is universal for
many low water-soluble substances ranging from anticancer
drugs to anticorrosion agents, dyes and inorganic salts. The
multilayers can be easily further integrated with additional
functions, such as specific targeting ligands. This may
represent a novel approach to conveniently formulate poorly
soluble drugs.
Drug controlled delivery systems based on polymeric bio-
degradable NPs are mostly investigated. Particularly, bio-
degradable and non-toxic polyester-poly(lactide-co-glycolide)
(PLGA) is one of the commonly used polymers for drug
delivery.224,225 Modification of the NPs surface with targeting
molecules can enhance the drug concentration in the targeted
organs or tissues, and reduce the dosage and toxic side effects.
In order to effectively immobilize the ligands, the NPs should
possess enough number of active groups and are required to be
stable enough to allow the chemical reactions. The LbL
assembly can endow the NPs with multi-properties such as
uniform surface charge density, numerous active groups and
excellent stability in various mediums. In this regard, macro-
molecules-coated PLGA NPs with a size of about 300 nm are
fabricated via an O/W emulsion-solvent evaporation method
by adding PEI or BSA in the water phase. PAA/PEI and
CS/alginate (CS/ALG) are then used to build multilayers on
the PLGA NPs for further immobilization of PEG and folic
acid aiming at long time circulation and targeting.226,227
Release property of the dyes preloaded in the NPs is greatly
affected by surface charge and structure of the multilayers
assembled on the NPs.228 A negatively charged or PEGylated
surface can reduce protein adsorption too, whereas surface
decoration with folic acid can enhance the NP uptake by
human hepatoma cells.
The multilayers also can be assembled on the NPs before
drug loading. This strategy allows the loading of different
drugs into the preformed multilayers-coated particles. Shutava
et al. reported the LbL multilayers-coated gelatin NPs with a
size of 200–300 nm as a vehicle for delivery of natural
polyphenols.229 Using the post-loading strategy, diverse natural
polyphenols are encapsulated and their biological activity is
retained. In our recent work,230 BSA NPs with a size of about
200 nm were coated with PAH–PSS multilayers, onto which a
layer of PAH-g-PEG–COOH is further adsorbed. By conden-
sation of carbodiimide chemistry aptamer-AS1411 molecules
which can target over-expressed nucleolin on the cancer cell
membrane231,232 are then immobilized (Fig. 15). The PEGylated
multilayers-coated BSA NPs show good suspension stability in
diverse mediums in particular serum containing medium.233 By
a mechanism of spontaneous deposition, DOX is effectively
loaded into the pre-formed BSA NPs with both good encapsu-
lation efficiency (98.6%) and loading percentage (9%). The
loaded drugs show a pH-dependent release behavior, i.e. faster
at pH 5.5 than at pH 7.4. The multilayers coating does not
bring significant influences on both drug loading and release.
Fig. 14 (a) Schematic representation of ultrasonication-assisted LbL assembly using the top-down approach. Ultrasonication is applied to break
down the paclitaxel powder and re-aggregation is prevented by adsorption of polyelectrolytes. (b) Schematic representation of ultrasonication-
assisted LbL assembly using the bottom-up approach. Nanoparticulation of paclitaxel dissolved in ethanol solvent is initiated by ultrasonication
and with addition of aqueous polycations. Adapted from ref. 222 with permission from the PCCP Owner Societies.
Fig. 15 Schematic illustration to show the preparation process of
BSA nanoparticles coated with PAH–PSS multilayers and coupled
with aptamer AS1411. Reproduced from ref. 230.
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In vitro cell culture demonstrates that the as-prepared BSA
NPs are specifically delivered to liver cancer cells, leading to
higher cellular uptake and cytotoxicity.
6.1.3 Capsules squeeze through a confined capillary. As
mentioned above, most of the LbL capsules have a diameter
of a few microns, which are easier for preparation and
property manipulation compared with their nanometer-sized
counterparts.234 Thus, for application of intravenous injection
smaller capsules are generally designed. However, Nature
takes a different way. A fascinating characteristic of a red
blood cell (RBC) is its extreme reversible deformability under
physiological flow, so that it can easily pass through the
smallest blood capillary vessel (B3 mm). Generally, the size
of multilayer microcapsules is pretty big and is comparable to
that of human RBC (about 7 mm). It is conceivable that the
microcapsules have to face the same challenge of passing
through the blood capillary vessel as the RBCs do, if they
similarly circulate in the blood stream. Therefore, their
deformability and recovery after passing through a thin capillary
channel is of practical importance and highly deserved to
explore. One can imagine that if the capsules have proper
shape and flexibility, they may easily squeeze through narrow
capillary as well. Indeed, the deformability of polymeric
microparticles (mainly hydrogel microparticles) with different
shapes and sizes through a narrow constriction has been
studied under flow conditions. For example, Doshi et al.
fabricated 7 mm RBC-mimicking particles, which are flexible
enough to flow through narrow glass capillaries (5 mm inner
diameter) and able to recover to discoidal shape.235 Hayashi
et al. fabricated 3.5 mm biconcave disk-shaped particles by
electrospraying of cellulose derivative ethylhydroxyethylcellulose
(EHEC), which can maintain RBC-like shape after filtrating
through a membrane with a pore size of 1 mm.236 Haghgooie
et al. synthesized PEG hydrogel particles with different shapes
including disks, rings, crosses, and S-shapes, and demonstrated
the modes of particles’ passage through poly(dimethyl siloxane)
(PDMS) channels.237 Very recently, the mechanical properties
and flow behavior of large capsules (tens of microns) made of
cross-linked ovalbumin have been investigated by the Leclerc
group.238 However, for the multilayer capsules with a size
comparable to that of human RBC, little is known about their
deformation behavior under flow in a microchannel with a
smaller size,239 although the static deformation behavior has
been systematically studied under the press of a colloidal
probe240 or osmotic pressure.116,117 Recently, a first step toward
the multilayer microcapsules’ deformability under flow in a
confined microchannel has been attempted in our group by
using the spherical PAH–PSS microcapsules either pre-filled
with PSS or not (Fig. 16).241 The influences of capsules size, wall
thickness, cross-linking as well as the filling of PSS inside on
the deformation and recovery behavior of the capsules are
systematically investigated. It is the deformation extent but
not mechanical strength that governs the recovery ability of
capsules. The squeezed hollow microcapsules can recover
their original spherical shape when the deformation extent is
smaller than 16% (reversible deformation), whereas per-
manent physical deformation takes place at a larger deforma-
tion extent such as 34%. The capsules with a thicker wall
(or namely stronger mechanical strength) can better resist the
water flow-induced deformation with a slower passing through
rate. In sharp contrast, all the intact capsules pre-filled with
PSS can recover their original shape although the deformation
extent is as large as 47%. The spontaneously deposited dyes
are well retained after the deformation and recovery process.
To the best of our knowledge, it is the first time to disclose the
alteration of drug amounts in multilayer microcapsules after
squeezing through a constriction. Yet this is only the first step
toward the fabrication of RBC-mimicking multilayer capsules.
Nonetheless, the current results are important not only for
understanding of capsule properties but also for their practical
applications as drug delivery carriers. For example, the capsules
for injection application should have a smaller size and soft wall
structure, while those for embolization should have a stiff wall
which can clog the blood vessels with higher efficiency.
6.2 Biosensors
Because of the convenient and diverse protocols for integration of
assay elements, the LbLmicrocapsules and microparticles are one
of the ideal platforms for sensing applications. Another important
advantage is that the analyte-sensitive and reference fluoro-
chromes can be simultaneously incorporated into a same capsule,
allowing precise ratiometric measurements. The examples of
biosensors based on LbL microcapsules have been first demon-
strated by theMcShane group, with a focus on glucose as a model
analyte.35,242–248 More recently, this concept has been extended to
pH, ions as well as nitric oxide sensing.
The pH sensor based on LbL multilayer microcapsules was
first reported by Kreft et al.249 Mobile pH-sensors are developed
for monitoring the local pH inside living cells (Fig. 17). The
pH-sensitive, high molecular weight SNARF-1–dextran conjugate
molecules are doped into CaCO3 particles via a coprecipitation
method.250 Microcapsules are loaded with SNARF-1–dextran
after assembly of multilayers and subsequent core removal.
SNARF-1 exhibits a significant pH-dependent emission shift
from green to red under acidic and basic conditions, respec-
tively. Its unique spectral properties are maintained after
encapsulation as well. Therefore, pH change of the local
Fig. 16 Scheme drawing to show the structure of the microchannel
device by (a) top view and (b) side view. CLSM images of the 6.8 mm(c) and 8.6 mm (d) (PAH–PSS)5 microcapsules after being squeezed
through the microchannel with a height of 5.7 mm. The former can
recover its original spherical shape (c), while the latter keeps its
deformed shape (d). Adapted with permission from ref. 241. Copyright
2012, American Chemical Society.
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environments can be monitored by the SNARF-1-filled capsules
during their transition from alkaline cell culture medium to
acidic endosomal/lysosomal compartments of human breast
cancer cells and fibroblasts. Based on this pH sensor, a flow-
cytometry-based assay has been developed with which the
uptake of multilayer capsules can be quantified.251 Capsules
on the outer cell membrane emit red fluorescence due to the
alkaline pH of medium, whereas capsules internalized by cells
emit green fluorescence due to the acidic pH in the endosomal/
lysosomal/phagosomal compartments in which incorporated
capsules are located. Thus, by recording the fluorescence
intensities in the red and green channels the localization of
capsules associated with cells can be distinguished. More
detailed analysis of particle uptake can be quantitatively
achieved by this method too.251 The pH sensor also can be
used as an intracellular optical reporter for monitoring lyso-
somal pH changes upon stimulation by some agents.252
Other active or reporting agents can be integrated into the
multilayers and cores too, which are useful to follow the
processing of such particles within targeted cells. Recently,
Reibetanz et al. designed an LbL assembled, biopolymer-
based multilayer system by combining a transporter and a
pH sensor for monitoring intracellular degradation and
processing.253–255 For this purpose, calcium carbonate particles
are functionalized with fluorescein isothiocyanate-labeled PAH
(FITC–PAH) which allows identification of particle localization
in cell compartments of different pH.256 Plasmid DNA as a
reporter agent for drug release in the cytoplasm and dye-
labeled protamine (PRM) are integrated into biocompatible
and biodegradable PRM/dextran sulfate multilayers. Uptake
and processing of the particles by cells are investigated via flow
cytometry and CLSM. They found a clear connection between
expression of the fluorescent proteins and the particle localiza-
tion in the cells. The multifunctional LbL system has some
advantages over other available systems, such as monitoring
of the degradation and processing of the carriers in live cells
without the demand of additional cell-staining.
Using the similar encapsulation strategies, other types of
biosensors based on LbL multilayer capsules are fabricated
too. For example, ion sensors are obtained by encapsulation of
ion-sensitive fluorophores-conjugated dextrans into the multi-
layer microcapsules. Since the capsule walls are permeable to
ions, the fluorescence of the capsules is tuned by ion concen-
tration. Furthermore, additional fluorophores with different
emission wavelengths and being independent of ion concen-
tration can be co-encapsulated, allowing for more precise
ratiometric measurements.257 By incorporation of a unique
quantum dot (QD) barcode into their outermost walls as a tag
for identification of individual sensors, this kind of barcoded
sensor capsules can be used for multiplexed analysis of proton,
sodium, and potassium ions in parallel.258
Quantitative, kinetic, and spatial analyses of the extracellular
delivery of nitric oxide (NO) molecules from the endothelial cell
(EC) layer to the smooth muscle cell (SMC) layer of blood
vessels upon drug stimulation are crucial for pharmaceutical and
biomedical evaluations of hypertension and diabetes.259 By
embedding an NO fluorescent probe, 4,5-diaminofluorescein
(DAF-2), into porous silica microparticles followed by LbL
assembly of chitosan and dextran sulfate (DS), biocompatible
particles with high NO sensitivity are fabricated.260 When the
NO sensors are allocated into each cellular layer, they can
spatially and quantitatively analyze NO diffusion from the EC
layer to the SMC layer using a 3D artery model (Fig. 18).261 The
3D artery model is constructed through an in vitro hierarchical
cell manipulation technique by fabrication of a nanometer-sized
extracellular matrix (ECM) through assembly of fibronectin
(FN)–gelatin(G) LbL films on the surface of each cell
layer.262–264 During this process the NO sensors can be
incorporated into each cellular layer. A graded concentration
change of NO from the uppermost human aortic endothelial
cell (HAEC) layer to the underlying human aortic smooth
muscle cell (AoSMC) layer is then elucidated by 3D analysis
using CLSM, demonstrating the effectiveness of this strategy.
6.3 Bioreactors
Inspired by nature cells, capsules and vesicles are ideal model
systems for transportation, catalysis and protection.265 The
LbL multilayer capsules are particularly suitable for such kinds
of investigations due to their precisely controllable structures
and functionalities.25 The LbL microcapsules are first employed
to encapsulate enzymes for bio-mineralization,266,267 enzyme-
catalyzed polymerization,268,269 and bienzyme reaction.270,271
Although most of the reactions take place inside the capsules,
they can be indeed performed in the multilayer walls as well.272
Li and co-works recently constructed a type of bienzyme
microcapsules,273 exemplified by hemoglobin/glucose oxidase
(HB/GOD capsules)274 and catalase/GOD (Cat/GOD capsules)275
Fig. 17 SNARF-loaded capsules change from red to green fluores-
cence upon internalization by MDA-MB435S breast cancer cells.
(A) SNARF-fluorescence after adding the capsules to the cell culture
and 30 min equilibration. Most of the capsules were outside of the cells
and exhibited red fluorescence due to the alkaline pH of the medium.
(B) The same cells after another 30 min of incubation. Capsules
remaining in the cell medium retained their red fluorescence (red arrows).
Capsules that were already incorporated into the acidic endosome in the
first image retained their green fluorescence (green arrows). Some
capsules were incorporated into endosomal/lysosomal compartments
inside cells within the period of 30 min, which is indicated by their
change in fluorescence from red to green (red to green arrows). Both
images comprise an overlay of microscopy images obtained with phase
contrast, a red and a green filter set. (C) Schematic presentation of the
endocytotic capsule uptake. Reproduced from ref. 249.
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through GA-mediated covalent LbL assembly.67 Both of the
systems are glucose-sensitive and can be used to control the
release of encapsulated insulin.
More recently, the individual polymerase chain reaction
(PCR) has been performed in LbL multilayer microcapsules
(‘‘Microcapsule-PCR’’).276 In this method, the first step is to
encapsulate PCR reagents, such as polymerase, primers and
templates, which are all macromolecules. Briefly, the PCR
reaction mixture and a matrix material (agarose) are emulsi-
fied at relatively high temperature to form microdroplets and
then cooled down to form solid agarose microbeads. LbL
assembly of multilayers on the microbeads leads to encapsula-
tion of the PCR reagents. Due to the semi-permeability of the
multilayer wall, during the PCR low-molecular-weight building
blocks, nucleotides (dNTPs) can diffuse freely into the interior,
while the resulting high-molecular-weight PCR products are
trapped inside the microcapsules. This microcapsule–PCR system
has good stability against annealing, and the individual micro-
capsule compartment does not exchange templates or primers
between each other. A similar strategy is also employed to
synthesize RNA in polymer hydrogel microcapsules.277
The encapsulated DNA also can be enzymatically degraded
under external stimuli.278 This reaction can be carried out in
a synthetic micro-reactor constructed by coencapsulating
double-stranded DNA and enzyme DNase I in multilayered
polymeric capsules. The semipermeable nature of the capsule
wall affords control over the reaction with added low-
molecular-weight chemicals, and the reaction is restricted
inside the capsules. This reaction is the first example of a
triggered degradation of DNA within a polymer reaction
vessel, which may mimic the lysosomal degradation of proteins
and nucleic acids within living cells.
The recent advances in fabrication of highly sophisticated
microcapsules with subcompartments offer new opportunities
for manipulation of more complicated reactions inside cap-
sules, which can better mimic cell functions.38,151 The first
example is the LbL microcapsules with a shell-in-shell structure
for integrated and spatially confined enzymatic reactions.140
Such two-compartment capsules exhibit exciting potential for
biomedical reactions in a confined small space. The barriers
between the integrated components can be remotely removed,
enabling mixing and, hence, the start of a reaction by an
external trigger.279 More recently, significant progress in the
bio-reactions in multi-compartmental microcapsules has been
made by the Caruso group.146,147,151,280–282 They developed a
strategy to incorporate intact liposomes into the LbL capsule
walls or inside the capsules to prepare ‘‘capsosomes’’.
Enzymes are loaded into the liposomes with well retained
activity. The enzyme reactions are triggered either by increasing
temperature to the phase transition temperature of the lipo-
somes, resulting in a disordered phase of the lipid membrane and
thereby allowing substrates to cross the membrane,147,281,282
or simply by adding surfactants to destroy the liposomes and
release the enzyme (Fig. 19).144 In the former strategy, the
encapsulated enzymes can be utilized repeatedly in several
subsequent conversions. More sophisticated capsosomes with
triggered cargo release property are also designed by coencap-
sulation of glutathione reductase-loaded liposomes and
disulfide-linked polymer–oligopeptide into capsosomes.281
The unique architecture of the capsosomes enables conversion
of oxidized glutathione to its reduced form by the encapsu-
lated glutathione reductase under elevated temperature. The
reduced glutathione can subsequently induce the release of
encapsulated oligopeptides from the capsosomes by cutting
the disulfide linkages of the conjugates. This study highlights
the potential of capsosomes to perform complicated enzymatic
reactions. Yashchenok et al. also reported a multi-compartmental
colloidal system by decorating a larger CaCO3 microparticle
with smaller liposomes. The CaCO3 microparticle and lipo-
somes are separately loaded with enzyme and the corre-
sponding substrate. Enzymatic reaction can be then triggered
by disruption of liposomes by ultrasonication.283
Adenosine triphosphate (ATP) synthase (ATPase) is called
‘‘molecular motor’’, and plays an essential role in the activities
of cells and regulates specific functions through their stimuli-
responsive mechanical motions.284 Integration of such natural
active proteins into engineered biomimetic microcapsules
results in novel properties and functions. Li and co-workers
Fig. 18 Schematic illustration of the in vitro spatial and quantitative analyses of NO diffusion from the uppermost EC layer to the SMC layer in a
3D artery model. Biocompatible sensor particles with high NO sensitivity are allocated into each layer. Reprinted with permission from ref. 261.
Copyright 2011, Wiley-VCH.
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first demonstrated the integration of chloroplastic ATPase
into the microcapsule wall containing a lipid bilayer and
synthesis of ATP by this composite capsule.285,286 The driving
force for ATP synthesis catalyzed by ATPase is provided by an
acid–base transition between the interiors and exteriors of the
capsules. Later on ATPase is also integrated on lipid-coated
hemoglobin287 or glucose oxidase288capsules. ATP can be
synthesized in protein microcapsules by utilizing proton gradients,
which are produced from oxidation and hydrolysis of glucose
catalyzed either by added or the immobilized GOD. The most
recent advance reported by the same group is the construction of
an active biomimetic system by integrating kinesin, microtubule,
and biomimetic microcapsule. The LbL multilayer capsules are
coated with kinesin, which can drive cargos such as vesicles,
proteins, and organelles along microtubules.289–291 Thus, the
microtubules act as tracks for the kinesins which are attached
on capsules, and guide the capsules to move from minus to plus
end. Both of the hollow and filled capsules as cargos are
transported by kinesin motors along microtubules (Fig. 20).292
In their following work the multilayer microcapsules are
attached to microtubules through biotin–avidin interaction,
which act as shuttles to transport the attached microcapsules.293
These approaches provide the great promise to design complex
hybrid nanodevices by using biological motors for mimicking
efficient intracellular transport.
7. Conclusions and outlooks
The LbL assembly technique has become a highly versatile and
powerful platform for fabrication of capsules with tailored
structures, compositions, properties and functions. The
as-prepared capsules have shown their great promise of appli-
cations in many areas of science and technologies. In parti-
cular, recent efforts have been made on the multilayer capsules
assembled by new driving forces and those with highly
sophisticated structures for biomedical applications, including
but not limited to drug carriers, biosensors and bioreactors, as
highlighted in this critical review.
Fig. 19 (a) Temperature-triggered enzymatic conversion. An increase in temperature to the phase transition temperature (Tm) of the liposomes
results in a disordered liquid phase of the lipid membrane, allowing nitrocefin to cross the membrane to be hydrolyzed while retaining the
b-lactamase inside the compartments. Reprinted with permission from ref. 282. Copyright 2010, American Chemical Society. (b) Surfactant-
triggered enzymatic conversion. The enzyme b-lactamase is preloaded into liposomes and is sandwiched between two cholesterol-modified
polymers, which are then embedded inside a polymer capsule. Upon addition of Triton X, the liposomes are destroyed and the enzyme is released,
thus causing the hydrolysis of nitrocefin. Reprinted with permission from ref. 144. Copyright 2009, Wiley-VCH.
Fig. 20 (a) Schematic illustration of a multilayer capsule as a cargo is driven by kinesin motors along a microtubule. (b) Time-lapse images of a
hollow capsule coated by kinesin motors moving along a microtubule. Adapted with permission from ref. 292. Copyright 2009, Elsevier.
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Although the past decade witnessed the significant advances
in this area, challenges are still remaining. First of all, new
fabrication strategies should be always pursued to obtain
capsules with novel structures and properties, which can fulfill
the requirements of new applications. For example, the recent
advances in multi-compartmental capsules have provided new
opportunities for bio-mimicking of the natural cells, resem-
bling some cellular processes in man-made particulate systems.
Particularly, the methods which combine the advantages of
precisely controllable structures and properties with speed-up
and scale-up production processes are highly welcomed. This
is also crucial for the real applications of LbL capsules.
Considering the applications of LbL capsules in biomedical
fields, drug delivery vehicles may be the most possible one in
the near future. However, to reach this aim many obstacles
should be pierced through besides the more efficient fabrica-
tion methods. For example, the in vivo tests of LbL capsules
have been only performed very recently215,294–296 and their
in vivo behavior such as degradation and toxicity is largely
unexplored. Since intravenous injection is the most convenient
way for the in vivo administration of LbL capsules, they are
required to circulate in the bloodstream and have good hemo-
compatibility. Several recent research studies have shown that
coating of blood-compatible multilayers on the ultra-small
(B20 nm)297,298 and submicron (B500 nm)299 particles is
beneficial to obtain injectable capsule drug delivery systems.
Therefore, particles with a submicron size are attractive for
preparation of LbL capsules, which may accumulate in
cancerous tissues through the EPR effect. But the assembly
of multilayers on nano- or submicron size templates is much
more difficult than on their micron-size counterparts. The
conditions for assembly should be carefully adjusted. In sharp
contrast, Nature takes a different strategy for facile passing
through a capillary vessel. RBCs possess the fascinating
characteristic of extreme reversible deformability under physio-
logical flow, and can easily pass through the smallest blood
capillary vessel (B3 mm). Inspired by this fact, the LbL multi-
layer microcapsules with suitable shape, size and flexibility may
mimic the behavior of RBC. Although the first step toward this
aim is attempted,241 more efforts should still be made. Further-
more, integration of specific functional moieties onto the
capsule surface, for example, targeting delivery, can enhance
the bioavailability and reduce side effects. On the basis of model
systems300,301 and in vitro experiments,230,302–304 the efficacy
should be further verified in vivo.
The newly developed fabrication strategies allow for design of
theranostic and synergistic drug delivery systems as well. The
theranostic carriers contain both drug and imaging agents within
a single system. This structure allows the carrier to selectively
accumulate in diseased tissues and simultaneously report their
biochemical andmorphological characteristics, while the synergistic
carriers which carry chemo-, radio- and gene therapeutics can
enhance the treatment efficacy.305,306 Apparently, the carrier
systems need co-encapsulation of various functional species with
a precise control over their structures and properties, which can
be fulfilled by the combination use of LbL and other techniques.
For example, the newly fabricated capsules with multi-
compartments and/or optical sensing ability are ideal candidates
for multi-drug delivery as well as theranostic systems.
Nowadays knowledge and techniques from more and more
multidisciplinary fields are applied to the research and appli-
cations of LbL multilayer capsules. It is undoubtedly that with
the efforts afforded by the experts from fields of chemistry,
materials science, physics, biology as well as pharmaceutics,
the above-mentioned challenges will be met sooner or later.
Meanwhile, with the diverse opportunities provided by new
fabrication strategies, more achievements in this field can be
expected in the future.
Acknowledgements
This study was financially supported by the Natural Science
Foundation of China (51120135001 and 21174130), theMinistry
of Science and Technology of China for the Indo-China
Cooperation (2010DFA51510), PhD Programs Foundation
of Ministry of Education of China (20090101110049),
Zhejiang Provincial Natural Science Foundation of China
(Z4090177 and Y4110064), and Open Project of State Key
Laboratory of Supramolecular Structure and Materials
(sklssm201224).
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