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DOI: 10.1039/D0BM00788A

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Design of Nanoengineered Antibacterial Polymers for Biomedical

Biomaterials Science Accepted Manuscript

Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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Applications
Qinggele Borjihana,b and Alideertu Donga,b,*
Pathogenic bacteria have become global threats to public health. Since the advent of antibiotics
about 100 years ago, their use has been embraced with great enthusiasm because of their effective
treatment of bacterial infections. However, the evolution of pathogenic bacteria with resistance to
conventional antibiotics has resulted in an urgent need for the development of a new generation of
antibiotics. The use of antimicrobial polymers offers the promise of enhancing the efficacy of

antimicrobial agents. Of the various antibacterial polymers that effectively eradicate pathogenic
bacteria, those that are nanoengineered have garnered significant research interest in their design
and biomedical applications. Because of their high surface area and high reactivity, these polymers
show greater antibacterial activity than conventional antibacterial agents, by inhibiting the growth or
destroying the cell membrane of pathogenic bacteria. This review summarizes several strategies for
designing nanoengineered antibacterial polymers, explores the factors that affect their antibacterial
properties, and examines key features of their design. It then comments briefly on the future
prospects for nanoengineered antibacterial polymers. This review thus provides a feasible guide to
developing nanoengineered antibacterial polymers by presenting both broad and in-depth bench
research, and it offers suggestions for their potential in biomedical applications.

1． Introduction Moreover, nanoengineered materials can overcome the

The threat that microorganisms pose to human health and
environmental safety has become a serious concern.
Throughout the history of the human species, pathogenic
bacteria, fungi, and viruses have been the chief culprits in the
spread of the most serious infectious diseases. The advent of
antibiotics reduced morbidity and mortality rates, especially
ushered in the antibiotic era.1 Yet while many generations of
antibiotics have been developed, the emergence of drug-
resistant bacterial strains and resultant diseases have placed
substantial stress on public healthcare systems around the
world.2-6 In the face of drug-resistant bacteria, many
antibiotics are losing effectiveness. As the pace at which new
antibacterial agents are presently being developed can
scarcely keep up with the rapidity of bacterial resistance
development, there is growing recognition that a post-
antibiotic era is approaching, where the failure of antibiotic
therapy will have major societal and economic impacts.7, 8
Nanoengineering, fabrication of nanosized antibacterial
polymers achieved via the different nanotechnologies, has
increasingly been used to develop biomaterials for biomedical
applications.9 In terms of antibacterial applications, non-
nanoengineered strategies suffer from some shortcomings,
such as small specific surface area, low antibacterial efficiency,
single function, and so on. Owing to their large surface-to-
volume ratio and multifunctionality, nanoengineered materials
have a unique advantage over their bulk counterparts.10
barriers faced by traditional antimicrobials, especially for
fighting against bacterial resistance, because the unique
physio-chemical properties of nanoengineered materials, as
well as their multi-mode synergistic antibacterial performance,
offer them multiple pathways to inactivate bacteria.11, 12 Their
new, size-dependent mechanisms make nanoengineered
materials highly effective for treating and preventing
infectious diseases.12 Research into nanomaterials based on
inorganic and organic compounds for use in antibacterial
applications has made tremendous progress; these materials
include metal and metal oxide nanoparticles13, carbon-based
nanostructures14, black phosphorus nanosheets15, and
polymer nanomaterials16, 17, among others. Compared with
inorganic nanostructures, organic ones are safer, contain more
active groups, and have easily modified molecular structures.18
To date, many organic nanostructures are found to have
antibacterial activity, such as, quaternary ammonium,
chitosan, and biguanides..19-23
Compared with traditional small molecules, polymers
working as antimicrobial agents have unique characteristics,
including stronger antibacterial efficiency, no volatility, and
good chemical stability, and they cannot penetrate human
skin.24 Antibacterial polymers can be divided into two main
classes: polymers with inherent antibacterial activity, and
polymers that present antibacterial activity when
functionalized with active agents.25 The action mechanism of a

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polymer depends on the activity of its functionalized group.
For instance, the most widely used polymer, positively charged
quaternary, is polymerized from quaternary ammonium salt
monomer, interacts with the cell wall, and destroys the cell
membrane, leading to leakage of the intracellular components
and ultimately, cell death.26 Other examples include povidone
iodine and N-halamine, whose antibacterial activity arises from
a releasable antibacterial halogen.27
Antibacterial polymers alone or in combination with other
biocides are used as both contact and release disinfectants in
many fields. Examples include nitric oxide (NO)-containing
polymers,28 ROS release conjugated polymer,22 N-halamine,29
and povidone iodine,30 which kill bacteria via release of a
biocide, whereas quaternary ammonium and antimicrobial
peptides tend to disrupt the bacterial membrane and kill
bacteria without the release of active components.31, 32
Nanoengineering of polymers is currently the most
indispensable technology for antibacterial applications, and a
large number of techniques have been explored to produce
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nanostructured antibacterial polymers for biomedical use. In
this paper, we highlight recent advances in the research and
application of nanoengineered antibacterial polymers. First,
we will focus on the nanoengineering of antibacterial
polymers, including nanotemplate strategies, emulsion
polymerization, electrospinning, and self-assembly. The
bactericidal pathways followed by nanomaterials are
inherently dependent upon their shape, size and surface
chemistry, so we will also comment on related factors that
affect the materials’ antibacterial properties. Finally, we will
highlight key considerations in the design of nanoengineered
antibacterial polymers, such as avoiding bacterial resistance,
and achieving biocompatibility and biodegradability.
2. Synthesis of Nanoengineering Antibacterial
Polymers
2.1 Nanotemplating
The effectiveness of antibacterial agents is highly dependent
on their active surface area, so nanoscale antibacterial
materials show superior activity due to their smaller size and
larger surface area.33 However, in the process of constructing
nanostructured polymers, additional polymerization and
agglomeration can lessen their special properties, depending
on the particles size, composition, and structure.34, 35 Most
studies have utilized inorganic/organic nanostructured solid
templates to control the morphology and size of
nanoengineered antibacterial polymers, thereby preventing
additional polymerization and particle agglomeration.34
Nanotemplate strategies present the opportunity not only to
fabricate nanoscaled antimicrobial polymer particles but also
to endow the resulting materials with various additional
functions, such as recyclability, bio-imaging and some others.36
Inorganic nanoparticles with an initiator on their surface
can control the polymerization of target monomers on the
surface. Among inorganic templates, those made of silica
nanoparticles have several advantages, including
biocompatibility, chemical inertness, facile controllability, and
ease with surface functionality.37, 38 SiO2 nanotemplates are
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widely used for fabricating antibacterial materials. For
View Article Online
example, in previous work, we reported the design and
DOI: 10.1039/D0BM00788A
preparation of antimicrobial nanoparticles using colloidal silica
nanoparticles as the support with barbituric acid-based N-
halamine immobilized on the surface via seeded
copolymerization; the resulting material displayed strong
antibacterial capacity and long-term stability.39 In addition,
researchers employed the unique properties of templates to
realize the multi-functionalization of nanoengineered
Biomaterials Science Accepted Manuscript
polymers. In 2019, Tang and co-workers fabricated
multifunctional nanoagents that could be used for imaging and
killing pathogenic bacteria. The nanoagents were made of
fluorescent silicon nanoparticles (SiNPs) functionalized with a
glucose polymer and loaded with Ce6 (Fig. 1).40
Magnetic nanoparticles are also popular for creating
inorganic nanotemplates, as they can be manipulated by an
external magnetic field and reused multiple times.41 Magnetic
nanotemplates have been widely used in the biomedical field
due to their high surface area, convenient operation, high
efficiency, and easy recyclability.42 The magnetic nanotemplate
is encapsulated in an antibacterial polymer shell that gives the
particles stability and biocompatibility. Various polymerization
methods are used, including emulsion, suspension, or solution
polymerization.41 However, magnetic nanoparticles have some
major drawbacks, arising from magnetically induced
polymerization, such as surface oxidation, and functional
group deficiencies. These nanoparticles are therefore always
encapsulated with silica or polymer using various synthesis
methods, to prevent aggregation and surface oxidation and
thereby increase their stability. For example, in one of our
previous studies, 42 we fabricated recyclable antibacterial N-
halamine nanoparticles by coating magnetic silica
nanoparticles with N-halamine via radical polymerization. The
functionalized nanoparticles maintained 100 % antibacterial
capability against P. aeruginosa and S. aureus even after five
cycles. In another study, Lee et al. prepared bactericidal
magnetic nanoparticles by complexing iodine with poly(N-
vinylpyrrolidone) grown on the surface of silica-coated Fe3O4
nanoparticles via surface-initiated atom transfer radical
polymerization(ATRP) (Fig. 2).43
Nanostructured polymers can also be employed as
templates for antibacterial polymers. Using biocompatible
polymer templates eliminates the need for core dissolution,
which is a key step in maintaining the integrity of multilayer
composite nanoparticles. Tzanov’s group produced a bioinert
polymer nanoparticle, poly(methyl vinyl ether/maleic acid),
functionalizing their templates with multilayers of
biocompatible hyaluronic acid and antimicrobial amino-
cellulose using a layer-by-layer coating approach (Fig. 3).44 The
nanoparticals with amino-cellulose as an outermost layer
showed strong antibacterial efficiency against both Gram-
positive and Gram-negative bacteria. In addition, colloidal
polystyrene nanoparticles (PS NPs) are strong candidates for
colloidal templates due to their chemical and physical stability,
and more importantly, the ease with which they can be
modified with various functional groups.45, 46 A typical example
is the work of Gao’s group, 45 which involved synthesizing PS
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coated silica nanoparticles (PS-SiO2 NPs) in the first step and
then anchoring cyclic N-halamine onto PS-SiO2 NPs. The as-
synthesized NPs displayed 2-8 times higher antibacterial
activity against both Staphylococcus aureus (S. aureus) and
Escherichia coli (E. coli) than their bulk couterparts.
Given the wide range of nanomaterials available,
nanotemplate strategies have become increasingly common in
biomedical applications. But whether a template is inorganic
or organic, once the nanoparticles enter the body, they
encounter a highly complex environment where they need to
identify and eliminate foreign elements.47 Adding specific
targeting mechanisms can reduce the uptake of non-specific
nanoparticles, further improving the nanomaterial’s efficacy.
Engineering nanoparticles with a template that enables them
to ignore everything except for their target, which has proven
to be exceptionally difficult and complex. In response,
considerable effort has been put into bioinspired
nanotechnology, which endows nanoparticles with unique
properties and has shown excellent potential in biomedical
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applications, as the resulting particles have inherent sensitivity
and specificity.47, 48
As fundamental units of biology, cells carry out a wide
range of functions and have the remarkable ability to interface
and interact with their surrounding environment.47 Instead of
attempting to replicate such functions via tedious technical
synthesis methods, it is easier and more effective to directly
leverage naturally derived cell membranes as nanotemplates
for fabricating antibacterial polymers. As seen in Fig. 4, Chen’s
group synthesized glycopolymers with high specificity for
binding to bacteria, using bacteria as living templates via
bacteria–sugar monomer-adaptation polymerization.49 This
provides a convenient and general strategy for preparing
synthetic glycopolymers with high specificity for the bacteria
used in their synthesis. It is expected that this technique will
process simple and convenient.58, 62 In 2014, our group
designed nanostructured N-halamine copolymerized
polystyrene via surfactant-free emulsion copolymerization,
then assessed the effect of monomer molar ratio,
temperature, and copolymerization time on the morphology
and size of the nanoparticles. The functional groups of
monomers can play a pivotal role in the design of
nanoengineered polymers by emulsion polymerization.63 N-
halamine homopolymers, for example, can be difficult to
obtain because of the radical autoinhibition effect of the allylic
structure.64 Given the challenges of synthetic nanoparticle
strategies, methyl methacrylate (MMA) is a good choice for
radical polymerization, because the ester group of MMA can
stabilize the radicals and promote the reactivity of allyl
monomers towards a chain propagation reaction. In this way,
MMA not only acts as co-monomer but also provides a
poly(methyl methacrylate) (PMMA) template for amine N-
halamine functionalized microspheres without using an
additive colloidal template.65
In addition to MMA, styrene (St) is another ideal
comonomer for achieving antibacterial polymer using
emulsion polymerization approach without any additives,
which makes the synthesis simple and convenient. For
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provide the basis for many future applications,View such asOnline
Article cell
labelling and capturing. Although glycopolymers may not
DOI: 10.1039/D0BM00788A
completely prevent bacterial colonization or completely
eliminate the negative effects of bacteria on normal cells, this
approach is expected to greatly improve antibacterial activity
by introducing bactericidal groups (such as Ag or quaternary
ammonium groups). In addition, these glycopolymers show
strong bacteriostatic ability and prevent bacteria from harming
normal cells in co-culture experiments. A variety of cells have
Biomaterials Science Accepted Manuscript
also been utilized as nanotemplates in biomedical applications,
such as red blood cells (RBC)50, 51, cancer cell membrane52,
macrophage membrane53, bacterial54, 55 and so on. Although
these biotemplates are relative new, it is a promising strategy
for engineering antibacterial agents.
2.2 Emulsion Polymerization
The introduction of nanotemplates can improve surface
activation, but there are also the unavoidable drawbacks of
cumbersome synthesis procedures requiring more reaction
steps, and the pollution caused by these templates during
practical application. Emulsion polymerization is widely used
to synthesize nanostructured polymers owing to simplicity,
environmental friendliness, and controllable particle size.56, 57
Driven by technological developments in recent years,
emulsion polymerization has led to new synthesis strategies —
surfactant-free, core–shell, miniemulsion, microemulsion
polymerization and others58-61 — leading some researchers to
use emulsion polymerization to design nanoengineered
antibacterial polymers.
The use of a surfactant in traditional emulsion
polymerization leads to low purity and performance in
antibacterial polymers, but surfactant-free emulsion
polymerization without further additives can avoid these
drawbacks and make the preparation
instance, Cai and coauthors fabricated amine N-halamine
copolymerized polystyrene nanoparticles as potent
antibacterial agents by using the surfactant-free emulsion
polymerization.66 The as-synthesized NPs possessed superior
antibacterial capabilities against both E. coli and S. aureus by
destroying bacterial surface structure. In Sun’s study, two
antibacterial polymer beads were prepared by polymerization
of styrene with 3-(4’-vinylbenzyl)-5,5-dimethyl-hydantoin
(VBDMH) and 3-allyl-5,5-dimethylhydantoin (ADMH),
respectively, followed by chlorine bleaching. Then their
antibacterial activities against gram-negative and gram-
positive bacteria were evidenced.67 Besides, St-based emulsion
polymerization approach is also successful in preparing
antibacterial povidone iodine. As typically reported in
previous, Gao et al., fabricated povidone iodine-conjugated
cross-linked polystyrene resins, i.e., P(St-DVB-NVP)-I2, using
emulsion copolymerization of St, divinylbenzene (DVB) and
vinyl-2-pyrrolidone (NVP), coupled with iodination reaction.68
They found the as-produced P(St-DVB-NVP)-I2 worked as an
antibacterial additive to remove pathogenic bacteria from
water.
2.3 Electrospinning Technique
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Electrospinning is a versatile and viable technique for
generating nanofibres. Over the past few decades, remarkable
progress has been made in engineering electrospinning
nanofibres to suit or enable various applications, and it has
proven to be a flexible and convenient technique for preparing
antibacterial nanofibres that have large specific surface area,
high porosity, and abundant active sites.69 Various polymers
have been electrospun into nanofibres as scaffolding
materials, such as polyacrylonitrile (PAN),70 poly(vinylidene
fluoride)
(PVDF),71 poly(methyl methacrylate) (PMMA),72 poly(glycolic
acid) (PGA),73 poly(lactic acid) (PLA),74 polystyrene (PS),75
poly(ε- caprolactone) (PCL),76 poly(vinyl alcohol)(PVA),77
polydopamine (PDA),78 and Polycarbonate urethane (PCU).79
In recent years, electrospinning has been recognised as a
feasible technique for fabricating antibacterial fibrous
composites by incorporating functional materials. Antibacterial
polymeric electrospun fibres are typically engineered using
one of two techniques. The first, surface immobilization,
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involves a two-step process: electrospinning to obtain neat
polymeric fibres from a solution, and followed by deposition of
the antimicrobial components. This avoids the loss of
antibacterial active components during the electrospinning
process. N-Halamine-containing polymer fibre can be
synthesized in this way. 72 Specifically, the N-halamine
precursor polymer is prepared by electrospinning, then the
nanofibres are halogenated (Fig. 5a). In the second technique,
the polymer solution is electrospun together with the
corresponding antibacterial components; this process can
include core-shell encapsulation,80 colloid-electrospinning,77
and nanoparticle-decorated nanofibres.81
As evidenced in numerous studies, multifunctional
electrospun composite membranes exhibit enhanced
performance in antibacterial applications. For example, Xu et.
al developed nanoengineered membranes with growth-factor
and antibiotic-delivery capabilities to achieve dual
functionality for efficient guided tissue regeneration (Fig. 5b).
Mesoporous silica nanoparticles with large pores and the
ability to encapsulate and preserve the bioactivity of growth
factors were used as the core, and antibiotics were loaded in
polymer shell nanofibres via coaxial electrospinning.80 Jiang et
al. reported a new class of antibacterial multicompartment
nanofibrous material with a nanocapsule-in-nanofibre
structure. The design principle of the material consists of first
synthesizing nanocontainers loaded with functional payloads,
and subsequently embedding the capsules in a polymer
nanofibre using colloid electrospinning (Fig. 5c).77 A variety of
antibacterial materials have been electrospun into nanofibres,
such as N-halamine,82 Chitosan,83 silver nanoparticles,84 and
graphene oxide85. These have been incorporated into polymer
nanofibres by physical blending to achieve strong antimicrobial
activity.
Unfortunately, the majority of current polymeric medical
devices are prone to microorganism colonization, and in the
case of electrospun materials, this propensity can be increased
by the larger surface area available to interact with
microorganisms. Adhesion of microorganisms eventually leads
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to biofilm formation, the predominant mode of View microbial life
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due its inherent resistance to antimicrobials. 86-88 Hence, when
DOI: 10.1039/D0BM00788A
developing antimicrobial electrospun nanofibres, it is crucial to
determine how this interaction can be avoided. To address
such challenges, various modifications have been studied to
give nanofibres antifouling abilities. Several antifouling
polymers, including hydrophobic,89 hydrophilic,90
zwitterionic,91 and amphipathic molecules, 92 have been
introduced into electrospun materials.
Biomaterials Science Accepted Manuscript
Fluorinated and other hydrophobic polymers have a low
surface energy, which minimizes the intermolecular
interactions between the fluorine (or other groups) surface
and fouling materials.93 In typical, Chen et al. developed a
poly(vinylidene fluoride) (PVDF) nanofibrous membrane
modified with multi-arm amphiphilic flexible poly(p-phenylene
terephthalamide) (f-PPTA). The modified membrane showed
remarkable improvement in antifouling and antibacterial
activity.71 For hydrophilic polymers, the mechanism of
antifouling is a result of water molecules binding to the
polymer, creating a protective hydrated surface that reduces
interactions between the foulant and the surface.94
Poly(ethylene glycol) (PEG), a common hydrophilic polymer,
has shown good antifouling properties in biomedical
applications.94 Polymer zwitterions have also emerged as a
promising class of antifouling materials. Charge-neutral
zwitterionic moieties attract water to the surface, forming a
hydration layer that is likely responsible for excellent protein
adsorption resistance and reduced bacterial adhesion.95
Amphiphilic polymers, which are a combination of
hydrophilic and hydrophobic polymers, have shown effective
antifouling properties. Typically, the hydrophobic segment
prevents biofoulants from adhering, while the hydrophilic
segment is able to release biofoulants that have managed to
be adsorbed.92 Cho et al. described fabricating amphiphilic
triblock terpolymer-based fibres by electrospinning a solution
of poly(lactic acid) and synthesizing amphiphilic triblock
terpolymers. The resulting fibres had amphiphilic polymer
groups and exhibited superior antifouling performance
compared to fibres without such groups.96
2.4 Self-Assembly of Amphiphilic Polymers
Polymer self-assembly has been a hot research topic for
several decades because the polymer on its own or hybridized
with antimicrobial agents has the potential to increase
antimicrobial activity, has good biocompatibility, and is easy to
prepare at the nanoscale level.97, 98 Amphiphilicity refers to a
balance between hydrophobicity and hydrophilicity, which is
affected by the chemical properties of various molecules. For
antibacterial polymers, hydrophilic or target function polymers
are more suitable for cell binding, but a hydrophobic domain is
essential to break through the cell wall and achieve insertion
into the membrane.92, 99 Consequently, the structural design of
these antimicrobial polymers is crucial.
There is a wide variety of fabrication strategies for
amphiphilic self-assembling polymers, including
homopolymerization,100 random copolymerization,101 and
block copolymerization.102 Amphiphilic homopolymerization is
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a relatively facile method of polymer self-assembly. However,
the resulting single structure limits its antibacterial properties
and applications. To this end, Wang and colleagues prepared
geminized amphiphilic cationic homopolymers containing both
double hydrophilic groups and hydrophobic moieties in each
structural unit. These geminized amphiphilic cationic
homopolymers not only had higher charge density, which was
conducive to adsorption on the cell membrane, but also
demonstrated strong hydrophobic interactions between the
long hydrophobic chains of the homopolymer and the
liposomes of the bacterial membrane, thereby destroying the
membrane much more efficiently.103 The most common self-
assembling polymers are copolymers with two or more
functional units.
The structure of amphiphilic copolymers is of great
importance for the polymer–membrane interaction. The
antibacterial activity and membrane disruption mechanism of
amphiphilic copolymers can be controlled through the
amphiphilic copolymer structures. In random copolymers,
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hydrophilic and hydrophobic groups are spaced
unsystematically along the polymer backbone. In comparison,
block copolymers have regular hydrophobic and hydrophilic
distributions along the polymer backbone, and their
hydrophobic/hydrophilic balance is controllable.97 The
structure of an amphiphilic copolymer is a key determinant of
its antibacterial and haemolytic activities. Some of the factors
affecting the haemolytic activity of synthetic amphiphilic
polymers have recently been explored. Oda et al. examined
the antibacterial and haemolytic activities of a series of
amphiphilic block and random copolymers of poly(vinyl ether)
derivatives. Block and random copolymers with similar
polymer lengths and monomer compositions displayed the
same level of bactericidal activity. The block copolymers
displayed selective activity against E. coli over red blood cells
(RBCs), while the random copolymers did not and were
haemolytic. Liposome dye leakage experiments showed that
the block copolymers selectively disrupted the bacteria-type
membranes over the erythrocyte-type membranes, whereas
the random copolymer did not show any selectivity.104
The location and length of the hydrophobic and cationic
moieties on a polymer structure determines the antimicrobial
activity and therapeutic selectivity of the resulting
nanomaterial. In 2018, Rotello and co-workers synthesized a
library of quaternary ammonium poly(oxanorborneneimides)
possessing different degrees of hydrophobicity and assessed
their antimicrobial and haemolytic activities (Fig. 6). These
polymers form nanoparticles 10-15 nm long in aqueous
solution, increasing their overall cationic charge and molecular
mass. This work observed that longer hydrophobic alkyl chains
that bridged the cationic headgroup and polymer backbone
led to greatly enhanced toxicity against planktonic bacteria
while maintaining low haemolytic activity toward RBCs. These
nanoparticles readily penetrated biofilms and eradicated
preformed biofilms while still maintaining high therapeutic
indices.105 In all of these cases, the polymer structure has
amphiphilicity induced by an appropriate hydrophobic and
hydrophilic balance, and the polymer chains can self-assemble
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into advanced nanostructures. Encapsulation of View hydrophobic
Article Online
compounds within the hydrophobic domains of nanomaterials
DOI: 10.1039/D0BM00788A
allows these water-insoluble molecules to be dispersed in
aqueous solutions.
Polymeric micelles also offer opportunities for delivering
hydrophobic antibiotics to fight against bacterial infections.
bacteria rather than mammalian cells and can insert into the
bacterial membrane, resulting in physical membrane damage
(Fig. 7).106 Li’s group developed a drug-loaded amphiphilic
Biomaterials Science Accepted Manuscript
copolymer that enable VAN-mediated bacterial targeting as
well as drug release in response to pH and lipase signals at the
infection site (Fig. 8).107 In another study, self-assembled
fluorescent-conjugated polymer nanoparticles (CNPs) forming
a “saccharide bridge” were developed by Wang’s group, and
effective accumulation on P. aeruginosa was leveraged to
efficiently kill bacteria through reactions with toxic singlet
oxygen from photosensitized CNPs based on their unique
bifunctional surface groups; fluorene units and phenyl groups
acted as a conjugated backbone with hydrophobicity and ROS
generation, and two side chains (phenylboronic acid (PBA) and
quaternary ammonium (QA)) projecting from the backbone
possessed hydrophilic and bacteria-binding features (Fig. 9).108
All in all, nanoengineered amphiphilic polymer fabricated via
self-assembly strategy enable to endow antibacterial agents
with multiple functions at the same time, as a result improving
antibacterial efficiency, reducing cytotoxicity and avoiding
drug resistance.
3. Factors Impacting the Antibacterial Properties
of Nanoengineered Polymers
Nanoengineered antibacterial polymers can be synthesized by
a wide variety of methods. To enhance their antibacterial
activity, a large number of studies have investigated how to
design ideal antibacterial nanoparticles. Overall, the size and
shape of the resulting nanoengineered polymer are important
to consider when trying to achieve high antibacterial
effectiveness.
3.1 Size
The size of antimicrobial agents has been demonstrated to be
a key factor in their efficacy. Specifically, biocidal efficiency
depends on the exposed active area of the biocide.11, 109 From
this viewpoint, reducing the size of biocidal polymers is a
potential solution for enhancing their antimicrobial efficiency.
During the last decade, nanosized antimicrobial
macromolecules have been reported to display enhanced
antimicrobial activity against bacteria when compared with
their bulk counterparts 34, 109 As is generally accepted, the size
effect on antimicrobial activity is essentially attributed to the
relationship between specific surface area and activity. Dong
et al. studied the correlation between antibacterial activity and
surface area. The results show that with the increase of
specific surface area, the antibacterial activity of N-halamine
modified polystyrene nanoparticles increased, indicating that
the larger the specific surface area of N-halamines, the
stronger the antibacterial activity. In their work, the surface
area calculation was performed according to the following
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equation: S = 6 (D∙d)-1, wherein S is the surface area (m2∙g-1); D
is the diameter ( μ m) and d is the density (g∙cm-3) of the
nanoparticles (Fig. 10).63 Also, the antimicrobial efficacy of
size-controllable quaternary ammonium functionalized silica
nanoparticles against Gram-negative E. coli as well as Gram-
positive S. aureus and D. geothermalis increased with
decreasing nanoparticle size110. In order to improve
antibacterial activity, Jang and Kim sought to reduce biocide
size. They encapsulated colloidal SiO2 NPs with N-halamine
polymers, and the as-formed core-shell NPs demonstrated
size-dependent antibacterial activity.111 Antimicrobial
nanoparticles provide distinctive advantages over conventional
antibiotics, not only in enhancing bactericidal activity but also
in lowering production costs and overcoming bacterial
resistance. Their very small size is also crucial for their
penetration through biofilms to prevent the development of
drug-resistant bacteria.
3.2 Shape
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A number of recent studies have pointed out the
importance of a nanoparticle’s shape in its antimicrobial
efficacy, investigating polymers such as spheres, rods, fibres,
and sheets. Research has proven that a rough or prickly
surface shows stronger antibacterial ability than smooth
surfaces.112 Ma and coworkers synthesized poly(o-
aminophenol) containing phenolic hydroxyl groups and their
microstructures were controlled by tuning polymerization
conditions. The possible formation mechanism of the
microstructures follows the prickly-fluffy-full sphere growth
process. The final antibacterial statistic demonstrated that the
microstructures affected their antimicrobial properties. The
prickly sphere-like structures showed excellent antibacterial
activity against the bacteria due to their high contact area, the
antibacterial properties of phenolic hydroxyl and polyaniline
molecular chains, and the additional bactericidal effect of
nano-needle-like structure.112 Using spheres and fibres of N-
halamine nanoengineered polymer, Kang et al, compared the
antibacterial activities of electrospun fibres with those of
spheres made by emulsion polymerization (Fig. 11).82 The
results demonstrated showed that nanofibres had better
activity than nanospheres, in part because of the fibres
“effective” contact time. Fibre products randomly dispersed in
bacterial solution can act as a “filter”, thus increasing the
“effective” contact time between bacteria and antibacterial
materials and thereby yielding better antibacterial ability. In
another study, Almeida et al. designed cationic peptide
amphiphiles that self-assembled into supramolecular
nanostructures such as micelles, nanofibres, and twisted
ribbons. Their results suggested that the peptide amphiphile
micelles disrupted the bacterial membrane more efficiently
than nanofibres, killing bacteria via a mechanism of action
associated with membrane disruption. This was because the
micelles’ lower stability in comparison to nanofibres meant
they acted as a monomer reservoir; the micelles’ disassembly
led to lipophilic tail intercalation into the membrane and
subsequent bacterial death.113 Overall, shape-dependent
antibacterial activities arise because (i) shape affects the
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specific surface area of nanostructured polymers,View and (ii)Online
Article the
mode of interaction between nanostructured polymers and
DOI: 10.1039/D0BM00788A
bacteria depends to some extent on the polymer’s shape. The
shape of antibacterial polymers synthesized by different
methods also yields different antibacterial effectiveness.
4. Key Factors When Designing Nanoengineered
Antibacterial Polymers
Biomaterials Science Accepted Manuscript
4.1 Avoidance of Bacterial Resistance
Bacterial resistance to antimicrobial materials is a major
problem that obviously limits the scope of a given antibiotic’s
utility. It is therefore imperative to identify and develop
innovative strategies for antimicrobial treatment that will
circumvent the evolution antibiotic-resistant bacteria. A
membrane-disruption mechanism is one effective way to kill
bacteria with little chance of triggering drug resistance.18
Various materials and strategies combined with
nanotechnology have been developed to eradicate bacteria.
For instance, antimicrobial peptides, quaternary ammonium
salt, povidone iodine, and others have been demonstrated to
be more potent and less conducive to drug-resistance because
they act through membrane disruption.114-120 In addition,
different methods can be exploited to reduce the possibility
that microbes will become resistant to the particular weapons
used against them. Some examples are targeted antibacterial,
antibiofilm, and on-demand release of antibiotics. Recently,
Rotello and co-workers fabricated bactericidal polymer
stabilized nanosponges through the self-assembly of
synthetically engineered polymers around essential-oil-based
cores (PONI–GMT). The polymers served to stabilize the
emulsion and enhance the interaction with bacteria due to
their positive charge. These nanosponges were degradable in
the presence of endogenous biomolecules such as glutathione
and esterase enzymes. The nanosponges (~220 nm) showed
high stability in serum and retained their activity even after
one year of storage. They disrupted the bacterial membrane,
eventually causing cell death. Notably, the bacteria were
unable to develop resistance against the nanosponges after 20
passages, whereas the MIC of conventional antibiotics
increased more than a thousand-fold in fewer passages (Fig.
12). 121
In an on-demand release system, an external stimulus
triggers the polymer to release antimicrobial agents on
demand to avoid unnecessary exposure of the antibacterial
materials to the environment, thus preventing the
development of drug resistance. Bacterial infections generally
feature very low pH (~4.5) values, so the acidic environment of
bacterial infectious sites can be harnessed in the design of pH-
sensitive drug delivery systems.122 The increased expression of
enzymes at infectious sites, including esterases and
gelatinases, also provides an effective strategy for the delivery
of antimicrobials via an enzyme-triggered mechanism.123 Due
to the abundance of pore-forming bacterial toxins at infected
sites, these toxins can be used to trigger the selective release
of antimicrobials from nanomaterial-based delivery vehicles at
the target site.124 This approach allows for the release of drugs
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to kill toxin-secreting bacteria at the infection site without
generating harmful side effects for healthy tissues. In 2019,
Wu et al. developed a bacterial toxin-targeted and oxygen-
triggered antibiotic release system utilizing liposome-based
nanoreactors (Fig. 13). To ensure biocompatibility, the
components used to fabricate the nanoreactors were obtained
either from natural sources or from FDA-approved
biocompatible polymers. The key mechanism was related to
the phase change temperature and the gas-triggered
sequential reaction. In this reaction, when the nanoreactors
made contact with the bacteria at 37 oC, the toxin became
anchored on the surface of the nanoreactors and penetrate
the layer of lecithin to form pores; H2O molecules then
entered the nanoreactors through the pores to react with
CaO2 and produce H2O2. Meanwhile, part of the H2O2
decomposed into O2 to drive the controlled release of
antibiotics.1254.2 Biocompatibility
Biocompatibility is crucial for antibacterial materials, so the
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material should not be toxic, injurious, or physiologically
reactive, or cause unwanted immune responses. Well-
designed biocompatible polymers therefore need to further
decrease the cytotoxicity of nanoengineered antibacterial
polymers. Antibacterial polymers exhibit varying degrees of
activity against different bacteria and mammalian cells; those
that show higher selectivity against the membranes of bacteria
are likely to have higher biocompatibility.126 Haemolytic
activity is conventionally used as a measure of cytotoxicity and
a model for mammalian cells because RBCs are, in general,
extremely fragile.127 Gao and Yang’s group reported a
biohybrid nanomaterial consisting of antibiotics, enzyme,
polymers, hyaluronic acid, and mesoporous silica
nanoparticles, which exhibited efficient in vitro and in vivo
antibacterial activity with good biocompatibility and negligible
haemolytic side effects.128 In another report, Ren’s group
developed novel antibacterial composite sponges from
chitosan incorporating N-halamine-modified ZnO
nanoparticles via a simple vacuum freeze-drying procedure. In
both in vitro cytotoxicity assays and skin irritation tests, the
designed composites showed high biocompatibility (Fig. 14).129
4.3 Biodegradability
Nonbiodegradable drug-loading polymers may persist and
accumulate within the body, causing unwanted side effects,
such as inflammation and carcinogenesis.121, 130 Hence,
designing a material that is biodegradable in the presence of
endogenous biomolecules such as glutathione and enzymes is
very important. In addition, when using nanostructured
polymers containing antibiotics, one way to curb the rise of
antibiotic resistance is to reduce the amount of antibiotics
while increasing their bioavailability.131 To achieve this,
traditional antibiotics can be coupled with various synthetic
polymers or encapsulated into polymer nanoparticles. The
payload of conjugates or microencapsulated drugs can be
enriched in the bacterial infection area and then released for
sterilization to achieve biodegradability.132 Gao’s group
designed a biodegradable antimicrobial cationic polymer that
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was functionalized with bacterial membrane anchoring and
View Article Online
destructive components; it had strongDOI:antibacterial activity
10.1039/D0BM00788A
against drug-resistant bacteria and connected hydrolytic esters
together to achieve considerable biodegradability.133 This
antibacterial substance was hydrolysed through the action of
ubiquitous lipase, which changed its bactericidal activity from
exuberant to inert, thereby avoiding chronic exposure to the
bacteria and minimising the possibility of antimicrobial
resistance developing.
Biomaterials Science Accepted Manuscript
In vitro antibacterial polymer materials present the
potential risks of white pollution and other environmental
problems caused by the polymers remaining in the
environment. Newly developed materials not only are able to
resist bacterial growth but also are biodegradable in the
environment to minimise their ecological impact. Ren et al.
produced polyhydroxybutyrate/poly(butyleneadipate-co-
terephthalate) (PHB/PBAT) nanofibrous membranes with
electrospun blends of biodegradable PHB and PBAT. Then 1-
allylhydantoin (AH) and perfluorooctyl acrylate (PFA) were
grafted onto the PHB/PBAT, producing nanofibrous
membranes with good antibacterial ability, excellent
hydrophobicity, environmental friendliness, and good stability,
making them useful as food packaging and biomedical
materials.134
5. Conclusion and Perspective
In the present era of bacterial drug resistance to conventional
antibiotics, and escalating concern about a post-antibiotic era,
there is a pressing need to combat resistance and discover
novel antibiotics. This review has provided an overview of
recent developments in nanoengineered antibacterial
polymers for biomedical applications.
Thanks to the efforts of numerous research groups, a wide
variety of molecular design strategies for nanoengineered
antibacterial polymers have been developed. The
nanotemplate strategy endows antibacterial polymers with
unique properties that facilitate the formation of nanoparticles
with well-controlled size, shape, structure, stability, and
additional functions. Commonly used nanotemplates include
organic and inorganic solid nanoparticles. In addition,
bioinspired nanotemplates are becoming widely used to
design biomedical materials that have specific targeting
mechanisms and good biocompatibility. Compared with the
nanotemplate strategy, emulsion polymerization is simpler,
more environmentally friendly process. Electrospinning
nanofibres are also widely applied antibacterial materials
owing to their large specific surface area, high porosity, and
abundant active sites. Self-assembled nanostructures can
significantly improve the antibacterial efficacy resulting from
structure-dependent, highly concentrated antibacterial agents.
Of further interest are “smart,” multifunctional
nanostructured polymers that can be designed using a self-
assembly strategy.
The size and shape of nanoengineered polymers are
important to consider for controlling their antibacterial
properties. Presently, it is more difficult to regulate the size
J. Name., 2013, 00, 1-3 | 7
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ARTICLE
and shape of nanostructured antibacterial polymers than
those of inorganic materials, and to date, there is relatively 7.
less research in this area.
Molecular design strategies show strong potential for
developing materials that can effectively combat bacterial
infections. In addition to improving antibacterial efficiency and 8.
expanding the areas in which these materials can be applied,
we urgently need design methods that can be tailored to
achieve high selectivity for bacteria and overcome drug 9.
resistance. The biocompatibility and biodegradability of
antibacterial nanomaterials are also important issues for in
vivo biomedical applications, so further work is needed in that 10.
area to develop appropriate materials.
Although nanoengineered antibacterial polymers have 11.
made remarkable achievements till now, it is worth noting that
there are still some challenges in this promising area, including
(i) compared with inorganic antibacterial nanomaterials, there
are few studies focusing on morphology and size control when 12.
designing nanosized antibacterial polymers; (ii) up to now, the
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approaches to obtain nanoengineered antibacterial polymers 13.
are very few, and it is urgent to explore an efficient and simple
nanoengineering strategy; (iii) a variety of in vivo evaluation
models should be developed on demand for real-world 14.
applications; (iv) transforming the bench research on
nanoengineered antibacterial polymers in academic 15.
laboratories into practical applications by developing close
collaboration between scientists and front-line workers. It is 16.
reasonable to hope that the nanoengineering of antibacterial
polymers may provide an alternative way to design
antibacterial materials that are more efficient, have a lower 17.
probability of inducing bacterial drug resistance, have higher
biocompatibility, and will be feasible for practical applications. 18.
Conflicts of interest
There are no conflicts to declare. 19.
Acknowledgements
This research was supported by the National Natural Science
Foundation of China (21304044 and 51663019), the Natural 20.
Science Foundation of Inner Mongolia Autonomous Region
(2015MS0520 and 2019JQ03), the State Key Laboratory of
Medicinal Chemical Biology (201603006 and 2018051), the 21.
State Key Laboratory of Polymer Physics and Chemistry (2018-
08), and the Program of Higher-Level Talents of Inner 22.
Mongolia University (30105-125136).
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126. Y. Su, L. Tian, M. Yu, Q. Gao, D. Wang, Y. Xi, P. Yang, B. Lei, DOI: 10.1039/D0BM00788A
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130. N. Kamaly, B. Yameen, J. Wu and O. C. Farokhzad, Chem.
Rev, 2016, 116, 2602-2663.
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Biography:

Biomaterials Science Accepted Manuscript

Alideertu Dong is a full professor at the College of Chemistry and Chemical Engineering, Inner
Mongolia University. He is the director of Engineering Research Center of Dairy Quality and Safety
Control Technology, Ministry of Education. His research focuses on the development of
antibacterial materials, particularly their synthesis and application. To date, he has published three
books and over 50 peer-reviewed papers.
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Qinggele Borjihan is currently pursuing her Doctor’s degree in chemistry under the supervision of
Professor Alideertu Dong at Inner Mongolia University. Her current work focuses on the design and
synthesis of iodine-containing polymer for biomedical applications.

Address:

a. College of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot 010021, People’s Republic of China

b. Engineering Research Center of Dairy Quality and Safety Control Technology, Ministry of Education, Inner Mongolia University,

Hohhot 010021, People’s Republic of China

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Figures：

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Fig. 1 Design of multifunctional nanoagents for detection and photodynamic treatment of bacterial infections. a Synthetic route
of nanoagents of GP-Ce6-SiNPs. GP-Ce6-SiNPs are composed of SiNPs conjugated to GP and loaded with Ce6 molecules. b
Imaging and treatment of Gram-negative and Gram-positive bacterial infections by GP-Ce6-SiNPs. GP-Ce6-SiNPs are robustly
internalized by ABC transporters, which are only present in bacterial cells whilenot present in mammalian cells. Under 405-nm
excitation, GP-Ce6-SiNPs exhibit two typical emission maxima peaks at 520 nm (assigned to SiNPs) and 670 nm (assigned to Ce6).
Under 660-nm irradiation, ROS of 1O2 is produced from Ce6, triggering PDT against bacteria. Ref. 40. Copyright (2019) Nature.

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Fig. 2. Schematic illustration of the preparation of bactericidal magnetic nanoparticles MNPs@PVP–I. Adapted with permission
from ref. 43. Copyright (2015) Royal Society of Chemistry.

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Fig. 3. Schematic illustration of the polymeric nanoparticle template decoration in an LbL fashion. Adapted with permission from
ref. 44. Copyright (2018) American Chemical Society.

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Fig.4. Scheme of the polymerization in the presence of bacteria: two different polymers were obtained: (1) in solution (SP), (2)
on the surface of bacteria (BP). Adapted with permission from ref. 49. Copyright (2019) American Chemical Society.

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Fig.5. Scheme of (a) Process of the synthetic strategy to create as-spun N-halamine-containing polymer fibers. Adapted with
permission from ref. 72. Copyright (2016) American Chemical Society (b) Process of Multifunctional Electrospun MSNs-
Encapsulated Core−Shell Nanofibers with Growth Factor and Antibiotic Delivery Ability for GTR. Adapted with permission from
ref. 80. Copyright (2020) American Chemical Society (c) The design consists in first synthesizing nanocapsules loaded with
functional payloads and subsequently embedding the nanocapsules into polymer nanofibers by using the colloid-electrospinning
technique. Adapted with permission from ref. 77. Copyright (2016) American Chemical Society.

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Fig.6. (a) Molecular structures of oxanorbornene polymer derivatives. (b) MIC values of polymer derivatives with different
hydrophobic chain lengths. Log P represents the calculated hydrophobic values of each monomer. (c) Schematic representation
depicting self-assembly of P5homopolymers. Characterization of P5 PNPs using TEM imaging and DLS measurement. (d) Graph
for FRET experiments between P5Rhodamine Green and P5-TRITC indicating formation of polymeric NPs. Adapted with
permission from ref. 104. Copyright (2018) American Chemical Society.

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Fig.7. The polymeric antimicrobial micelles can physically destroy the integrity of bacterial membrane, resulting in the leakage of
intracellular milieu, synergistically strengthening the photodynamic bacteria eradication upon light irradiation. Adapted with
permission from ref. 105. Copyright (2019) American Chemical Society.

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Fig.8. (a) Synthesis procedures of Van-hyd-PECL amphiphilic copolymers. Van-hyd-PECL is obtained by conjugation of CH3CO-
PECL with Van-hyd. CH3-CO-PECL is prepared by ring opening polymerization of ε-CL using acetyl-terminated PEG (CH3-CO-PEG)
as initiator. Van-hyd is synthesized by the reaction of carboxyl group of VAN with hydrazine. (b) Micelle formation, bacterial
targeting, and drug release from VanhydPECL micelles. After VAN-mediated bacterial targeting, the VAN shell is removed from
the micelles via the cleavage of hydrazone bonds under acidic conditions, and the PCL core is degraded by lipase overexpressed
at the infection site, followed by CIP release and bacterial destruction. Adapted with permission from ref. 107. Copyright (2018)
American Chemical Society.

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Fig.9. Schematic illustration of saccharide bridge binding between P. aeruginosa and PFPPBA CNPs for enhanced bacterial killing
efficiency. Adapted with permission from ref.108. Copyright (2020) American Chemical Society.

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Fig.10 Reduction of bacterial colonies (P. aeruginosa and S. aureus) upon the 60 min exposure to the N-halamine-based PS
nanoparticles with different surface area. ref. 63. Copyright(2014) Elsevier.

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Fig.11. (A−C) Formation Process and (D) Morphology Transformation of N-Halamine Fibers Using the Combined
Copolymerization−Electrospinning−Chlorination Technique. Adapted with permission from ref. 82. Copyright (2015) American
Chemical Society.

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Fig.12. (a) Cross-linked PONI-GMT-DTDS structure showing linkage points reactive to endogenous biomolecules. (b) DLS
histogram of crosslinked PONI-GMT-DTDS nanosponges loaded with carvacrol. in phosphate buffer saline (150 mM). (c) Chemical
structures of PONI-GMT and (d) DTDS. (e) Confocal micrograph of crosslinked micron-sized biodegradable composites. PONI-
GMT labeled with TAMRA-X (red fluorescence), and the oil core is loaded with DiO (green fluorescence). A composite
morphology is indicated by codistribution of PONI-GMT with the hydrophobic oil core. Scale bar is 3 μm. Adapted with
permission from ref. 121. Copyright (2018) American Chemical Society.

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Fig.13. Design and characterization of liposome-based nanoreactors. a The scheme of endogenous stimulus-powered antibiotic
release from RFPCaO2@PCM@Lec nanoreactors for bacterial infection combination therapy. b The solid PCM was dissolved in
melted PCM at 37 °C. c Differential scanning calorimetry (DSC) curves of LA and SA. d A typical TEM image of the RFP-
CaO2@PCM@Lec nanoreactors. e UV absorption spectra of RFP under different conditions. Free RFP (black), RFP in ethanol (red),
in toxin (blue) and in DI water (green). f FI-IR absorption spectra of different materials. g Mapping of RFP-CaO2@PCM@Lec
nanoreactors. Source data are provided as a Source Data file. Adapted with permission from ref. 125. Copyright (2019) Nature.

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Fig.14. Schematic interpretation of the design and preparation procedure for the CS/ZnO-PSPH-Cl dressing. Adapted with
permission from ref. 129. Copyright (2019) American Chemical Society.

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Table:
Table 1. Schematic illustrations for some typical nanotemplate strategy

Biomaterials Science Accepted Manuscript

Bacteria
Antibacterial Polymer Template Typical Imaging Ref
Species
Poly(4-(allyloxy)-2,2,6,6- SiO2 S. aureus 37
tetramethylpiperidine-co- P. aeruginosa
methyl methacrylate) based
N-halamine
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5,5-Dimethylhydantoin SiO2@PS S. aureus 43

based N-halamine E. coli

Poly(3-allyl-5,5- Fe3O4@SiO2 S. aureus 40

dimethylhydantoin-co- P.aeruginosa
methyl methacrylate) based
N-halamine

Antibacterial amino cellulose poly(methyl vinyl S. aureus 45

and polysaccharide ether/maleic) E. coli
hyaluronic acid

Polymethacrylamide based Iron oxide S. aureus 42

N-halamine E. coli

Glycopolymers E. coli MG1655 E. coli 47

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