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81
5
Regeneration of Bone-Related Diseases by Nucleic Acid-Based
Nanomaterials: Perspectives from Tissue Regeneration and
Molecular Medicine
Xiaoru Shao
Jining Medical University, Affiliated Hospital of Jining Medical University, Department of Stomatology, Guhuai Road,
Jining, Shandong 272029, PR China
5.1 Introduction
There are many types of bone-related diseases that seriously aect the quality of life of
patients. The dysfunction or loss of bone tissue function caused by inammation, injury,
trauma, disease, aging, or genetic disease not only brings great pain to the patient but
also brings a series of socioeconomic problems. Common bone-related diseases include
osteoporosis, osteoarthritis, bone metastases, osteomyelitis, myeloma, and bone defects
[1–5]. Bone-related diseases can seriously aect the quality of life of patients; therefore, it
is very important to seek eective treatment methods. Traditional bone tissue regeneration
treatment methods mainly include transplantation of autologous bone, allogeneic bone,
and articial bone. However, all of the above treatment methods have certain drawbacks
and limitations, such as increased risk of infection, rejection of recipients, and insucient
donors, which cannot fully meet clinical needs [6–8]. In addition, the patient’s economic
status and their acceptance of materials for repairing bone defects are also important
issues for surgeons to consider when repairing bone tissue defects [9]. Screening out new
materials with a better ability to repair bone tissue defects to meet clinical needs has
become an urgent problem for researchers and clinicians to solve. Bone tissue engineering
avoids the shortcomings of traditional biomaterials and explores new biomaterials through
continuous research on emerging technologies. The focus of bone tissue engineering
research includes stem cells, biomaterials, and growth factors. Bioscaold materials are
designed to mimic the extracellular matrix, providing a suitable microenvironment to
support and promote bone tissue growth. The bioscaold materials used should have
good biocompatibility, biodegradability, and low immunogenicity. Therefore, methods for
discovering simple synthetic biomaterials and improving the biosafety of materials need to
be explored. It is urgent to carry out in-depth research on biomaterials that can eectively
repair bone tissue regeneration.
Nanotechnology has attracted widespread attention since its emergence. Nanotechnology
refers to the study of the properties and technologies of materials in the range of 0.1–100 nm.
The unique small-scale eect, surface eect, tunnel eect, etc., make nanomaterials have
Nucleic Acid-Based Nanomaterials: Stabilities and Applications, First Edition.
Edited by Yunfeng Lin and Shaojingya Gao.
© 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.
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82 5 Regeneration of Bone-Related Diseases by Nucleic Acid-Based Nanomaterials
a wide range of application prospects and have achieved rapid development in the past
20 years [10, 11]. In particular, the application of nanotechnology in the elds of drug carri-
ers, biosensing, bioimaging, gene delivery, disease diagnosis, and treatment has been deep-
ened day by day. Nanomaterials, as new carriers for drug delivery, have many advantages
compared with traditional free drugs, including increased drug stability, controllable drug
release rate, reduced dosage, and improved bioavailability. It will become a hot research
eld in future medical development [12–14].
Nucleic acid nanotechnology is a new type of nanotechnology developed in recent years.
The principle of nucleic acid nanotechnology is to use nucleic acid and its derivatives as
basic materials. By designing highly specic and programmable base sequences, nucleic
acid molecules are folded and paired to form nanomaterials with specic shapes, geome-
tries, and scales [15, 16]. Due to the biomolecular properties of nucleic acid itself, it can
be used as a new type of transport carrier and may also carry specic genetic information.
Therefore, nucleic acid-based functional nanomaterials have special application prospects
and research value. Nucleic acid-based functional nanomaterials use the inherent nucleic
acid of the human body as the raw material, so they have many advantages, such as
good biocompatibility and degradation ability, being nontoxic to organisms, and having
rich functional modication sites. Nucleic acid nanotechnology has been widely used in
molecular diagnosis, biological imaging, molecular delivery, and targeted drug delivery
[17, 18]. Therefore, how to eectively regenerate bone tissue with nucleic acid-based
nanomaterials has become an interesting research direction. This chapter will review the
role of nucleic acid-based nanomaterials in bone-related disease regeneration from the
perspective of tissue regeneration and molecular medicine.
5.2 The Development Process of Functional Nucleic Acid
The development of nucleic acid nanotechnology has made nucleic acid widely used as
a material. By applying base pairing with highly specic and programmable properties, a
large number of framework nucleic acid nanomaterials with dierent dimensions, shapes,
and geometric structures can be perfectly designed and synthesized [19, 20]. Among
the many potential application directions of nucleic acid nanomaterials, biological and
biomedical applications are very attractive due to the biomolecular properties of nucleic
acids. Nucleic acid nanomaterials generally have low cytotoxicity and strong resistance
to enzymatic degradation in biological environments, which are favorable for the in vivo
application of nucleic acid-based functional nanomaterials. Since Watson and Crick
proposed the double helix structure model, the biochemical properties, structure, and
morphology of DNA molecules have been well studied. Nucleic acid nanotechnology
refers to nanotechnology based on the physical and chemical properties of DNA, which is
mainly used for molecular assembly to produce functional assembly aggregates. Therefore,
the research of nucleic acid nanotechnology occupies an extremely important position
not only in the eld of life sciences but also in the eld of nanomaterials [21, 22]. The
essence of nucleic acid nanotechnology is DNA self-assembly, and the core of self-assembly
is the principle of complementary base pairing. As a natural biological macromolecule,
DNA has unique advantages in constructing functional structures at the nanoscale,
including high specicity, predictability, programmability, high mechanical rigidity, and
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5.2 The Development Process of Functional Nucleic Acid 83
high physicochemical stability [23, 24]. Throughout the development of nucleic acid nan-
otechnology, it has been found that functional nucleic acids mainly include DNA tile, DNA
origami, three-dimensional DNA self-assembly, DNA nanorobots, and DNA microchips.
5.2.1 DNA Tile
In 1982, Seeman of New York University’s Department of Chemistry rst proposed that
two-dimensional ordered arrays could be constructed using branched DNA molecules
with complementary sticky ends [25]. The basic building unit of two-dimensional DNA
structure (also known as “DNA tile”) is a four-arm-junction complex constructed by
four single-stranded DNA, and the base sequences of the four sticky ends are specially
designed, and through the complementary pairing between the sticky ends in dierent
motifs, periodic two-dimensional DNA planar structures can be constructed [26]. Seeman’s
genius idea was later proven experimentally to be the rst stepping stone to structural
DNA nanotechnology. Early nucleic acid nanotechnology mainly studied various DNA
self-assembly modules and various periodic structures generated by their assembly. Based
on Seeman’s original idea, in 1999, Mao Chengde’s research group at Purdue University
connected four Holliday junctions together to construct parallelogram DNA structural
units, which could self-assemble to form a 2D DNA array with diamond-shaped holes [27].
Later, Yan Hao’s group reported a cross-shaped primitive, namely a 4 × 4 primitive, which
can be used as a template to form conductive nanowires or two-dimensional protein arrays
[28, 29].
5.2.2 DNA Origami
In 2006, Rothemund’s research brought an exciting advance in structural DNA nanotech-
nology. He rst proposed “DNA origami” in Nature: using more than 200 short DNA aux-
iliary strands, by folding M13mp18 genomic DNA, two-dimensional structures of about
100 nm in size and arbitrary shapes, such as rectangles, squares, triangles, stars, and smi-
ley faces [30]. In 2006, under the leadership of He Lin, an academician of the Chinese
Academy of Sciences, the Bio-X Research Institute of Shanghai Jiaotong University, pio-
neered the creation of a “DNA China Map” with a length of 150 nm, a width of 120 nm, a
thickness of 2 nm, and a resolution of 6 nm. The world’s rst asymmetric two-dimensional
DNA pattern overcomes the stress problem caused by asymmetric patterns [31]. The exper-
iment proves that asymmetric, complex, two-dimensional shapes can be constructed using
the method of DNA origami. They further deduced that DNA origami has the ability to
construct nearly any complex two-dimensional nanoscale shape. The advantages of DNA
origami self-assembly are that the design method is simple, the operation is easy, the raw
DNA does not need to be puried, complex patterns can be assembled in one step, and
the material yield is high. Combined with other methods and techniques, more complex
three-dimensional structures can be assembled through origami.
5.2.3 Three-dimensional DNA Self-assembly
When DNA self-assembly could easily build more complex planar graphics, scientists began
to pay more attention to building the three-dimensional structure of DNA. In the past ve
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84 5 Regeneration of Bone-Related Diseases by Nucleic Acid-Based Nanomaterials
years, research on 3D DNA nanostructures has achieved vigorous development, and a large
number of 3D DNA motifs have been successfully constructed. Turbereld’s group success-
fully constructed DNA tetrahedral structures of a series of sizes using four single-stranded
DNAs and tried to use these DNA tetrahedra as drug delivery systems for drug-controlled
release studies [32, 33]. Other 3D DNA nanostructures, including cube, tetrahedron,
octahedron, dodecahedron, buckyball, and nanotube, have also been extensively studied
[34–36].
5.2.4 DNA Nanobots and DNA Microchips
In a 2012 Science article, researchers used DNA origami to build a nanorobot that can
deliver tiny “cargo” loads to individual cells and aect their behavior [37]. The technique
folds DNA strands together into a complex shape with a cross section that resembles a
hexagon. They then loaded it with nanoparticles such as gold and uorescently labeled anti-
body fragments and watched their nanorobots deliver their cargo to cells in a tissue culture.
These nanoparticles can be designed to respond to certain cell surface proteins or specic
combinations of them and deliver a variety of dierent molecules that aect cell behavior
in dierent ways. In the new study, published in Nature on January 23, 2013, the scientists
“recorded” a 26-second clip of audio, a copy of a paper, a photo, and other information in
articially synthesized DNA [38]. The ndings mark a milestone toward the practicality
of using nucleic acids for storing information, which is more compact and durable than
current hard drives or magnetic tapes.
5.3 Nucleic Acid-Based Functional Nanomaterials
In addition to the abovementioned DNA-based nanostructures, functional nucleic acids
are combined with nanomaterials to form many functional nucleic acid nanomaterials.
Nucleic acid-based functional nanomaterials have the following characteristics: good bio-
compatibility, good biodegradability, good biological stability, and editability. Given these
properties of nucleic acid-based functional nanomaterials, they have promising application
prospects in biomedical applications such as drug delivery, tissue engineering, bioimaging,
and biosensing.
5.3.1 Nanomaterials That Can Bind to Functional Nucleic Acids
A wide variety of nanomaterials can be combined with functional nucleic acids, including
metal-based nanomaterials, carbon-based nanomaterials, biological nanomaterials, quan-
tum dots, and composite nanomaterials. Dierent types of nanomaterials combine with
functional nucleic acids in dierent ways and play dierent roles in bioimaging, biosensing,
drug delivery, tissue engineering, and other elds.
5.3.1.1 Metal-Based Nanomaterials
Metal-based nanomaterials are often combined with functional nucleic acids. This
combination enables functional nucleic acids with greater stability and new catalytic
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5.3 Nucleic Acid-Based Functional Nanomaterials 85
activities [39]. In addition, functional nucleic acids also enabled metal-based nanoma-
terials to have better biocompatibility and altered their charge properties. The most
basic combinatorial approach is to use metal-based nanomaterials as templates for
functional nucleic acid immobilization and localization. Functional nucleic acid-metal
nanomaterials have broad applications in biosensing, bioimaging, and biomedicine. At
the same time, functional nucleic acids also endow metal nanomaterials with more
precise targeting capabilities [40, 41]. The principle of nucleic acid template-forming
metal nanoclusters (NCs) is the process of nucleic acid metallization. Because the size
of NCs is very small, the surface energy is very high, and NCs are easy to gather, so a
stabilizer or matrix must be used to isolate NCs. Prior to the excellent work of Dickson
et al. using dendrimers as stabilizers, metal NCs were only prepared in low-temperature
inert gas or solid zeolite. After their initial discovery, Dickson’s team rst proved that
cytosine (C)-rich DNA can also stabilize uorescent AgNCs, which establishes a con-
nection between metal NCs and DNA. There is a strong specic coordination between
the N3 position of cytosine and Ag+, while the C-rich DNA strand shows a high an-
ity for Ag nanomaterials [42–44]. Subsequent work showed that all nucleotides could
participate in the binding of metal NCs. Each nucleotide has at least one metal binding
site. After further study, it was concluded that AgNC contains approximately the same
number of neutral silver atoms and silver cations, and these Ag species are arranged in
a rod-like structure rather than a plane or spherical structure. The existence of dierent
emission colors is attributed to the change in rod length caused by a specic alkali/Ag
interaction [41].
5.3.1.2 Carbon-Based Nanomaterials
The carbon nanostructures most commonly associated with functional nucleic acids
are graphene oxide (GO), carbon nanotubes (CNTs), graphene, and nanodiamonds [45].
Due to their large surface area, charge characteristics, and excellent electron transfer
ability, functional nucleic acids can be rmly immobilized on the surface of various
carbon-based nanomaterials. Functional nucleic acid-carbon nanomaterials are ideal
signal recognition elements for building uorescent biosensors [46, 47]. Functional nucleic
acids (FNA) can be rmly xed on the surface of various carbon-based nanomaterials.
The interaction between FNA and carbon surface may lead to signicant changes in some
biosensor signals. In addition, carbon-based nanomaterials have ecient uorescence
quenching ability. Therefore, FNA nanocarbon material is an ideal signal recognition
element for constructing uorescent biosensors [45]. Mesoporous silica nanoparticles
(MSNs) have ideal surface chemical properties, which make them easy to modify with
polycation. For example, MSNs modied with carbosilane dendrimers are used to deliver
oligonucleotides [48, 49]. In addition, the abundant hydroxyl groups on the surface of MSN
make it easy to functionalize into MSN-NH2, MSN-COOH, MSN-N3, and MSN-Cl. The
introduction of these groups makes the conjugation of FNA possible. The excellent surface
activity of MSNs is one of the primary qualities as nanomaterials. The new FNA-MSN
nanomaterial is an eective drug delivery material. The targeting ability of FNA makes the
probe or delivery system based on MSN have more accurate direction in vitro and in vivo
[50, 51].
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86 5 Regeneration of Bone-Related Diseases by Nucleic Acid-Based Nanomaterials
5.3.1.3 Bionanomaterials
Commonly used bionanomaterials are exosomes, which originate from the fusion of mul-
tivesicular bodies with the cytoplasmic membrane and are then released into the extra-
cellular space. Exosomes play an important role in the intercellular transport of proteins
and nucleic acids, which provides a theoretical basis for the combined application of exo-
somes and functional nucleic acid molecules [52]. Most exosomes can carry characteristic
molecules that certain cells can recognize, facilitating the selective targeting and adsorption
of recipient cells. The use of exosomes to deliver siRNA has emerged as a leading approach
for therapeutic gene regulation with good biocompatibility, low side eects, low immuno-
genicity, and reduced nucleic acid degradation [53, 54]. Most exosomes can carry some
characteristic molecules that can be recognized by cells, thus promoting the selective target-
ing and adsorption of receptor cells. Some exosomes also showed a strong ability to abscond
and identify, as well as to prevent the clearance or degradation of immune cells. Early stud-
ies have shown that small exosomes allow them to penetrate into tissues, so exosomes are
suitable as nanocarriers [54–57]. In addition, the exosomes showed slightly negative zeta
potential in long circulation, had a deformable cytoskeleton, and their membrane prop-
erties were almost the same as those of the cells themselves. Using exosomes to deliver
siRNA has become the main method for gene regulation. Because exosomes have good bio-
compatibility, no obvious side eects have been found in exosome-mediated gene delivery
systems used in vivo. This method avoids nonspecic delivery, prevents immunogenicity of
the delivery vector, and reduces nucleic acid degradation [58].
5.3.1.4 Quantum Dots
Quantum dots are semiconductor nanoparticles that are very small in size. So there
are quantum constraints in all three-dimensional spaces. Quantum dots can be divided
into several types, including metal-ion-doped inorganic semiconductor quantum dots,
metal nanoparticles and NCs, silicon quantum dots, carbon quantum dots, and graphene
quantum dots [59, 60]. Quantum dots have received extensive attention due to their
unique, highly sensitive optical and electronic properties [60, 61]. Functional nucleic acids
can be easily introduced into the surface of quantum dots based on their abundant surface
amino and carboxyl groups, and uorescence emission and quenching occur rapidly
between quantum dots and uorophores attached to functional nucleic acids. The above
properties make uorescent functional nucleic acid-quantum dot nanomaterials suitable
for bioimaging and biosensing [62, 63].
5.3.1.5 Magnetic Nanomaterials
Magnetic nanomaterials can be divided into magnetic beads (MBs), magnetic nanoen-
zymes, magnetosomes, and other magnetic nanomaterials according to their dierent
structural characteristics and applications. MB is the most widely used magnetic nanoma-
terial in biosensors and biomedicine. Polymer surface coatings play an important role in the
application of MBs with FNA. Although MB nanoparticles have no magnetic attraction due
to their superparamagnetic properties, they still have a signicant aggregation trend due to
their high surface energy. In addition, polymer coatings provide abundant binding sites for
FNA. For example, streptavidin can attach to the surface of MBs, and biotin-modied FNA
can connect to MBs through streptavidin–biotin interaction [64]. Bacterial magnetosomes
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5.3 Nucleic Acid-Based Functional Nanomaterials 87
are synthesized under strict genetic control, and bacterial magnetosomes have uniform
shape, size, dispersion, and chemical composition [65]. They allow cells to align passively
along magnetic eld lines, a behavior known as magnetotaxis [5]. In 2015, Borg et al. pre-
pared a ZnO/SiO
2
-encapsulated magnetosome core–shell heterostructure [66]. Compared
with the component materials, the new nanostructures have the following advantages:
the nanometer size of the magnetic body and the modication ability of silicon dioxide.
This makes it possible to produce FNA magnetosome composite nanomaterials by a new
construction method.
5.3.1.6 Composite Nanomaterials
The combination of composite nanomaterials is rich, and the core principle is to play on
the unique advantages of all nanomaterials [67]. For example, Jurado Sanchez and his
colleagues created a Janus micromotor, a composite nanomaterial composed of the semi-
conducting polymer polycaprolactone, graphene quantum dots, and Pt/Fe
3
O
4
. This Janus
micromotor can be driven only in the presence of H
2
O
2
or magnetic force without adding
other fuels. By coupling Janus micromotors with functional nucleic acids, a micromotor
probe with autonomous motion and capture capability can be synthesized, which can be
widely used in environmental and life sciences [68, 69].
5.3.2 Combination of Functional Nucleic Acids and Nanomaterials
Nucleic acid-based functional nanomaterials are composed of functional nucleic acids
(DNA tile, DNA origami, three-dimensional DNA self-assembly, DNA nanorobots, and
DNA microchips) and nanomaterials (metal-based nanomaterials, carbon-based nanoma-
terials, biological nanomaterials, quantum dots, and composite nanomaterials) formed by
self-assembly (Figure 5.1). There are various waysof combining functional nucleic acid with
Nanomaterials
Functional
Nucleic acid
Composite
nanomaterials
DNA
microchips
Carbon-based
nanomaterials
Metal-based
nanomaterials
Bio-nanomaterials
Quantum dots
DNA
origami
DNA tile
DNA
nanobots
3D DNA
nanostructures
Figure 5.1 Schematic diagram of the composition of nucleic acid-based functional nanomaterials.
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88 5 Regeneration of Bone-Related Diseases by Nucleic Acid-Based Nanomaterials
nanomaterials, including biological conjugation [70, 71], adsorption interaction [72, 73],
functional nucleic acid-template assembly [74, 75], functional nucleic acid-nanomaterial
heterojunction [76], and functional nucleic acid self-assembly [77–79], of which functional
nucleic acid self-assembly is the most noteworthy. Self-assembled DNA nanotechnology
constructs nucleic acid nanomaterials of dierent shapes and sizes, including tetrahedron,
octahedron, icosahedron, and other more complex DNA origami structures, based on the
“bottom-up” synthesis principle. Self-assembled nucleic acid nanostructures inherit many
advantages of functional nucleic acids, including small-scale eects, high programma-
bility, and excellent biocompatibility [80]. Self-assembled nucleic acid nanostructures
take the inherent DNA of human body as the raw material. Self-assembled nucleic acid
nanostructures have been widely used in molecular diagnosis, bioimaging, molecular
delivery, and targeted drug delivery due to their good biocompatibility and degradation
ability, nontoxic eect on organisms, rich functional modication sites, and many other
advantages. Self-assembled framework nucleic acid nanostructures are modied in a
variety of ways. For example, tetrahedral framework nucleic acid nanostructures (tFNAs)
are modied in vertex type, mosaic type, capsule type, and suspension type. There are
many kinds of groups and drugs that can be used to modify tetrahedral framework nucleic
acid nanostructures, including chemical polymers, aptamers, micro-RNA, PNA, LNA, and
traditional Chinese medicine monomers [81, 82]. These groups or drugs are connected
with tetrahedral framework nucleic acid nanostructures in dierent ways to construct new
nanomaterials with tFNAs as carriers, which can play a signicant role in the repair of
bone tissue defects [83] (Figure 5.2).
MSCs
Polypeptide
tFNAs
PNA, LNA
Traditional Chinese
medicine monomer
miRNA
Chemical
modication
Chemical
modication
Base pairing
Incubation
RNAi screen
Osteoblast
Small molecules that can promote
osteogenic differentiation of MSCs
Synthetic
tFNA-small molecule
compounds
Figure 5.2 Different combination of functional nucleic acids and nanomaterials.
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5.4 Multiple Roles of Nucleic Acid-Based Functional Nanomaterials 89
5.4 Multiple Roles of Nucleic Acid-Based Functional
Nanomaterials in Bone Tissue Repair and Regeneration
In view of the good molecular recognition and drug delivery capabilities of func-
tional nucleic acid nanomaterials, they have broad application prospects in the eld of
biomedicine, including the diagnosis and treatment of diseases. The molecular recognition
and drug delivery capabilities of nucleic acid nanomaterials can be widely used in the eld
of biomedicine, mainly in the diagnosis and treatment of diseases. Nanomaterials, such
as metallic nanomaterials and magnetic nanomaterials, have well-known advantages and
optical properties for synthesis, bioconjugation, injury imaging, and photothermal therapy.
Self-assembled 3D functional nucleic acid nanostructures, such as DNA origami and DNA
hydrogels, have good biocompatibility, stability, exibility, and precise programmability,
and are easy to synthesize and modify. In view of the above advantages of nucleic acid
nanomaterials, they have potential application prospects in the eld of bone tissue disease
repair and regeneration (Figure 5.3).
5.4.1 Sustained Release
The sustained-release eect of nucleic acid nanomaterials can avoid the sudden release
of drugs, slow down the rate of drug release, and achieve long-term treatment for better
ecacy. The nucleic acid nanomaterial sustained-release system has the following
Osteogenic
differentiation
Stem cell
Osteocyte
Osteoblast
Osteoclast
Sustained release
Extraction
Implant
ligature
(therapeutic)
Peri-implantitis
assessment
Bone targeting
Bioimaging of bone regeneration
Fluorescence
detection
Nucleic
acid-carbon dots
Bioimaging
Scaffold for bone regeneration
Mandibular
bone defect
ADSCsBone defect
model
Recellularized
mandible scaffold
Figure 5.3 Schematic illustration of the role of nucleic acid-based functional nanomaterials in
bone regeneration.
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90 5 Regeneration of Bone-Related Diseases by Nucleic Acid-Based Nanomaterials
advantages: First, the use of the nucleic acid nanomaterial sustained-release system can
reduce the frequency of administration and provide a more comfortable treatment process.
Second, the sustained-release system can achieve continuous release of drugs in the body,
thereby ensuring that the serum drug concentration has been maintained in a relatively
stable state. Third, some nucleic acid nano sustained-release systems have localized
eects, which can improve the eect of local treatment and reduce other systemic side
eects. To sum up, the nucleic acid nano sustained-release system can greatly improve
the therapeutic eect of drugs. Cui et al. applied lipid nanoparticles to carry TNF-α siRNA
to treat rheumatoid arthritis in mice. The results of the study found that the nucleic acid
nanosystem was an ideal sustained-release drug carrier because of its relatively high siRNA
encapsulation eciency (>90%) and low siRNA burst release rate (<5%). After intravenous
administration, the inammatory response in arthritic mice was signicantly reduced,
conrming that the sustained-release system has great application potential in the treat-
ment of rheumatoid arthritis [84]. The results of Zhao et al. showed that the tetrahedral
framework nucleic acid could enter mouse monocyte/macrophage cells without a carrier,
reduce the M1-type marker inducible nitric oxide synthase after lipopolysaccharide com-
bined with interferon-α treatment, and promote the induction of nitric oxide synthase. The
production of inammatory factors, nitric oxide, and reactive oxygen species increased,
and at the same time, the expression of M2-type markers arginase 1 and interleukin-10,
transforming growth factor-β increased, suggesting that tetrahedral framework nucleic acid
nanomaterials promoted post-injury healing and bone tissue remodeling while organizing
the inammatory response process. Further studies showed that the tetrahedral frame-
work nucleic acid nanomaterials promoted the M2-type polarization of macrophages by
regulating the phosphorylation of STAT in vitro and in vivo. The above experimental results
provide a theoretical basis for the tetrahedral framework nucleic acid nanomaterials as bone
immunomodulatory materials to support the regeneration of bone tissue at various stages
of bone healing [85]. Some studies have shown that miRNA-26a can promote bone regener-
ation through the positive regulation of angiogenesis–osteogenesis coupling. Li et al. devel-
oped a low-toxicity polymer (LP series) and a hyperbranched polymer (HP series) as miRNA
transfection system. By wrapping miRNA in polylactic acid glycolic acid sustained-release
microspheres, the microspheres were further connected to the L-polylactic acid nanoporous
scaold to build a local miRNA sustained-release system [86]. Due to the dierent molecu-
lar weights of polylactic acid and glycolic acid, the degradation rate of the sustained-release
system is dierent to achieve continuous release. In this study, miRNA-26a was embedded
into this slow-release system and implanted into the mouse skull defect model. The
experimental results showed that the compound miRNA slow-release system showed a
good ability to promote the repair of bone defects in situ [87, 88]. Based on the strategy
of embedding small RNA into scaold materials, some scholars also studied the targeted
modication of scaold materials to selectively bind target cells and release embedded
miRNA/siRNA, which is of great signicance for the treatment of bone-related diseases. It
has been reported that polyurethane nanomicelles modied with osteoblast-targeting pep-
tides can be used to encapsulate miRNA/siRNA and then used for osteoblast release [89].
The experimental results show that the SDSSD-PU delivery system not only selectively tar-
gets the bone formation surface but also selectively targets osteoblasts without signicant
toxicity and inducing an immune response. Anti-miR-214 was delivered to osteoblasts using
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