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181
10
Framework Nucleic Acid Nanomaterial-Based Therapy for
Osteoarthritis: Progress and Prospects
Yangxue Yao, Hongxiao Huang, and Sirong Shi
Sichuan University, State Ke y Laboratory of Oral Diseases, Wes t China Hospital of Stomatology, No. 14, 3rd Sec, Ren
Min Nan Road, Chengdu 610041, PR China
10.1 Introduction
Osteoarthritis (OA) is still one of the diseases that plague the world. It is a progressive dis-
ease in which the entire joint structure is altered. Patients with OA suer from severe joint
discomfort, with pain being the main symptom. In the early stages of the disease, pain is
triggered by intense physical activity and can be predicted. Over time, it becomes more dif-
cult to predict the pain and other joint symptoms that appear. Gradually, the pain becomes
more stable and begins to interfere with daily activities. In the late stages, the pain becomes
more severe, persistent, and unpredictable, leading to complete limitation of some activities
[1]. Associated symptoms include joint cracking, joint eusion, bone swelling, deformity,
and muscle weakness, which severely aect patients’ normal lives [2]. Currently, OA is a
major cause of disability burden. It is estimated that 300 million people worldwide suer
from OA [3]. In developed countries, medical expenditures for OA amount to 1 to 2.5%
of GDP, with joint replacement surgery accounting for the largest share of these medical
expenditures [4]. The individual costs of OA patients, such as lost income and the resulting
national burden, far exceed the cost of medical care [5, 6].
OA occurs most frequently in the knee joint, followed by the hip and wrist joints [7].
It is also closely related to systemic diseases. Existing studies have shown an association
between OA and atherosclerosis-related diseases [8]. Meta-analyses showed that people
with OA have a slightly increased risk of cardiovascular disease and stroke than people
without OA [9, 10]. In addition, more than half of older people with OA have hypertension,
followed by cardiovascular disease, dyslipidemia, and diabetes [10, 11].
10.2 Pathology of OA
The weight-bearing surface of the bone is covered with articular cartilage, which forms
an elastic, nearly frictionless layer that can spring back after deformation. However, the
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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182 10 Framework Nucleic Acid Nanomaterial-Based Therapy for Osteoarthritis: Progress and Prospects
Diagram OARSI grade Pathological features
Grade 1 Some chondrocytes showed
Surface intact apoptosis and necrosis
Surface discontinuity cell death
Loss of superfical matrix,Grade 2
Grade 3 Vertical clefts extends to
mid-zoneVertical fissures
Grade 4
Erosion
Matrix loss superficial and
mid-zone
Grade 5
Denudation
Subchondral bone exposed
Grade 6
Deformation
Subchondral bone is destroyed,
accompanying restoration
Figure 10.1 OARSI grade and pathological features in each grade. Source: Drawn by Figdraw.
articular cartilage is avascular and nerve-free, so it cannot spontaneously repair itself
when injured [12]. The pathological changes of OA aect the entire joint, including the
articular cartilage, subchondral bone, ligaments, joint capsule, synovium, and muscles
[13]. As shown in Figure 10.1, the degree of cartilage degeneration can be divided into six
grades according to the destruction of the articular tissue, which is referred to as OARSI
grade.
The pathological factors of OA are complex and include mechanical overload, inam-
mation, and altered metabolism, ultimately leading to structural destruction and loss
of function [14, 15]. OA is an active dynamic change caused by an imbalance between
repair and destruction of joint tissues. Most scientists believe that inammation plays a
crucial role in this process. To some extent, the deleterious eects of OA can be eliminated
or compensated for by altering the metabolic activity of chondrocytes. However, matrix
degradation occurs when these deleterious eects exceed the compensatory capacity of the
system [16].
Another possible explanation for OA is that cartilage degeneration causes immune
rejection within synovial cells, which may lead to the production of metalloproteinases
and inammatory cytokines, resulting in cartilage destruction [17]. Others theorize
that the innate immune system and activated synovial macrophages are involved in OA
development [17].
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10.4 Challenges for OA Therapy 183
10.3 Risk Factors of OA
OA has a strong genetic background [18, 19]. There are more than 80 genes involved in
the pathogenesis of OA. The contribution of genetics to OA has been estimated to be
40–80% [20].
Among the acquired factors, age is one of the major risk factors for OA. The increas-
ing incidence of OA with age is due to cumulative exposure to various risk factors and
age-related biological changes in joints, such as mitochondrial dysfunction and pathway
alterations [21, 22]. Pathological loading is another important factor. Poor alignment of the
knee joint, loss of the meniscus, repetitive stress injuries, and strenuous work activities can
cause joint damage [23]. In addition, hormonal balance and estrogen are closely related
to OA, making women more susceptible to developing it. Systemic factors such as obesity,
aging, metabolic disorders, and atherosclerosis also play important roles in the occurrence
of OA [17, 24].
It should not be overlooked that diet is also associated with OA.Patients who are decient
in vitamin C, D, and other trace elements have a higher risk of developing OA [25]. In
addition, OA can result from any inammatory events that lead to joint damage, such as
joint fractures, cartilage, ligament, or meniscus injuries [26].
10.4 Challenges for OA Therapy
Cartilage is the main load-bearing part of the joint; thus, frequent loading will inevitably
cause damage to it. Cartilage has no blood vessels or nerves. It has poor potential for spon-
taneous healing of lesions, resulting in clinical treatment challenges [27]. Many risk factors
cause OA, and treatments that target one factor alone always do not work well. Age, gender,
obesity, genetics, race, diet, and joint-related factors, including injury, joint alignment dis-
order, and abnormal joint loading, all might be the causative factors of OA. The interaction
of these risk factors brings a great challenge to therapy. Moreover, the mechanism of pain in
OA is complex, involving peripheral and central sensitization. This complexity may explain
why traditional painkillers (paracetamol, tramadol, and opioids) are relatively ineective
in relieving pain or improving function in OA [28].
Current medical interventions for the treatment of OA only relieve pain and perhaps
improve function, but have no eect on the onset or progression of the disease [29].
Nonsteroidal anti-inammatory drugs (NSAIDs) and acetaminophen are the rst-line
agents for OA. However, when used systemically, they must pass through the synovial
blood vessels to reach the local area. Therefore, extensive and prolonged usage is required,
and other organs are exposed to high drug concentrations, which increases the possibility
of undesirable side eects. In addition, current treatments based on direct intra-articular
injection of anti-inammatory drugs have short-term eects and unsatisfactory ecacy.
Drugs that act directly on chondrocytes must penetrate the dense and nonvascular extra-
cellular matrix, which limits their ecacy. Joint replacement surgery is the only option
for end-stage OA, although the associated risks of venous thromboembolism, infection,
neurovascular injury, and periprosthetic fracture are troubling. In addition, up to 25% of
patients complain of pain and disability even after replacement surgery [30, 31]. Alleviating
the progression of structural and symptomatic sequelae of OA has become the focus of
treatment development.
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184 10 Framework Nucleic Acid Nanomaterial-Based Therapy for Osteoarthritis: Progress and Prospects
10.5 Nucleic Acid Nanomaterial-Based Therapy for OA
Nucleic acids are the main material basis for the storage, duplication, and transmission of
genetic information, which is a fundamental part of life. Nucleic acid nanomaterials are
a general term for nucleic acids and their analogs, including oligonucleotides, plasmids,
aptamers, and DNA origami, which have independent structures and perform specic bio-
logical functions [32–34].
Nucleic acids are widely used in the biomedical eld, where they can regulate gene
expression by providing specic nucleic acids. Some nucleic acids enter into cells indepen-
dently. They remain in a specic location for a long time and are involved in transcription
and translation processes that can rebalance the metabolism of the OA cartilage. These
vector-independent nucleic acids include antisense oligonucleotides (ASOs), aptamers,
and tetrahedral scaold nucleic acids (tFNAs) [35, 36]. Some nucleic acids rely on vectors
to be introduced into cells or damaged compounds, such as messenger RNA (mRNA),
small interfering RNA (siRNA), and microRNA (miRNA) [37, 38]. In addition to gene
coding, many other interesting functions of nucleic acids have been discovered. For
example, it has been recognized that nucleic acid nanomaterials are well suited for drug
delivery, especially in complex conditions such as blood and cells [39]. Plasmids are the
traditional nucleic acid nanocarriers [40]. Aptamers have excellent targeting properties and
are promising nucleic acid nanocarriers. Moreover, the nucleic acid polyhedron formed
by DNA origami technology has intrinsic addressability, shape controllability, strong
penetration ability, and good biocompatibility [41]. They are widely used in biosensing and
biological therapy [42, 43].
Here, we will present a nucleic acid nanomaterial-based therapy for OA.
10.5.1 Vector-Independent Nucleic Acid Nanomaterials for OA Therapy
These materials have good penetration ability and stability, and they can enter cells without
vectors. For the convenience of readers, we have listed the relevant research papers from
the last ve years in Table 10.1.
10.5.1.1 Tetrahedral Framework Nucleic Acids (tFNAs)
Therapeutic Effects of tFNAs In 2004, Turbereld and his colleagues rst proposed a DNA
polyhedron in which tFNAs would be the simplest polyhedron. Based on DNA base pairing
Table 10.1 Vector-dependent nucleic acid nanomaterials for OA therapy in recent five years.
Nucleic acid Gene/target Cell used Animal used Ref
tFNAs Wnt/β-Catenin pathway Primary rat chondrocytes — [44]
tFNAs Nrf2/HO-1 Primary rat chondrocytes — [44]
tFNAs RhoA, ROCK2, and vinculin Primary rat chondrocytes — [45]
ASOs miR-34a-5p Human OA chondrocytes OA mice [46]
ASOs COX-2 Human OA chondrocytes — [47]
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10.5 Nucleic Acid Nanomaterial-Based Therapy for OA 185
and sticky-ended cohesion rules, tFNAs are synthesized from four single DNA strands
[43, 48–52]. Apart from their stable structure, tFNAs have attracted much attention
because of their good cell penetration and biocompatibility [53–58]. They can be readily
taken up intracellularly without transfectants in a nest protein-dependent manner [59].
Like natural DNA, tFNAs can scavenge ROS, which has been shown to protect damaged
cells and inammatory diseases [60–67].
In OA research, tFNAs have been found to be taken up by chondrocytes and regulate
cell proliferation, migration, and collagen secretion. The representative images are shown
in Figure 10.2. Shi et al. discovered that tFNAs could regulate chondrocyte autophagy and
maintain cellular metabolism and homeostasis. In their study, chondrocytes treated with
250 nM tFNAs showed accumulation of more autophagosomes. In addition, autophagy
genes were clearly upregulated by activation of the PI3K/AKT/mTOR pathway [69]. Shi
et al. also found that tFNAs promoted chondrocyte migration and increased the expression
of RhoA, ROCK2, and vinculin [45]. Shao et al. reported that chondrocytes treated with
250 nM tFNAs for 24 hours maintained their original round and three-dimensional
shape and exhibited signicant cell proliferation [61]. Subsequently, Shi et al. stimulated
chondrocytes with IL-1β to establish an OA model. They found that tFNAs could be taken
up by IL-1β-induced chondrocytes, and the uptake rate of chondrocytes for 250 nM tFNAs
was 72%. Later, they found that tFNAs could inhibit early and late apoptosis of cells and
downregulate the expressions of apoptotic proteins Bcl2, Bax, and caspase-3. Under IL-1β
stimulation, the production of ROS in chondrocytes increased and they were susceptible to
damage, whereas after treatment with tFNAs, ROS signicantly decreased and oxidative
stress was reduced. This is because tFNAs signicantly increased the expression of Nrf2
and HO-1, a critical signaling pathway for the maintenance of intracellular homeostasis
[44]. In addition, tFNAs increased the autophagy body and protein expression of the
autophagy-related marker LC3-II in IL-1β-induced chondrocytes. tFNAs inhibited the
Wnt/β-catenin signaling pathway and decreased the occurrence and development of OA,
as well as the associated proteins β-catenin, Lef1, and CyclinD1 [48]. The mechanism of
regulation of chondrocytes by tFNAs is detailed in Figure 10.3.
Biodistribution of tFNAs In recent works, tFNAs have passed through the cell membrane via
endocytosis [61]. Studies by Fan showed that the endocytosis process of tFNAs is mediated
by caveolae and micropinocytosis [70]. The onset time was dierent in the dierent cells
and ranged from 3 to 12 hours [71, 72]. The fate of tFNAs ends in lysosomes. Tian et al.
discovered that tFNAs entered L929 and A549 cells after 6 hours and were digested in lyso-
somes after 24 hours [73]. Exocytosis of lysosomes is a promising process for the pathway
of tFNA out of cells.
Regarding systemic biodistribution in animals, tFNAs accumulated preferentially in
the kidney, liver, and gallbladder after injection via the tail vein of mice [65]. In addition,
there were also uorescently labeled tFNAs in the brain, indicating that they can cross
the blood-brain barrier. tFNAs that entered the brain were stable for at least one hour
[74]. The signal intensities in kidney and liver started to decrease after one hour. More
tFNAs accumulated in the kidney than in the liver one hour later, indicating preferential
renal clearance over hepatic metabolism. tFNAs subsequently appeared in the bladder for
excretion from the body [54].
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186 10 Framework Nucleic Acid Nanomaterial-Based Therapy for Osteoarthritis: Progress and Prospects
0.0
250 125
Exposure concentration of tFNAs
62.5
200
150
100
50
0
3.0
Control
tFNAs
Normalized Cell Index
Cell proliferation (%)
2.5
2.0
1.5
1.0
0.5
0.0
5.0 10.0 15.0 20.0 25.0
Time (in Hour)
30.0
CH control
CH 62.5nM DNA
CH 125nM DNA
CH 250nM DNA
35.0 40.0 45.0
Self-assembled
95°C 10 min, 4°C 20 min,
Cytoskeleton
Merge DAPI Collagen II
Control
tFNAs
tFNAsssDNAs(a)
(b)
(d)
(e)
(f)
(c)
0 h
24 h
Control
tFNAs
250 nM tFNAs 125 nM tFNAs 62.5 nM tFNAs Control
DAPI LC3 Actin Merge
25 um
25 um
Figure 10.2 Effect of tFNAs on chondrocytes. (a) Schematic graph for the synthesis of tFNAs.
(b) Cell proliferation detected by CCK-8 assay after treating chondrocytes with tFNAs for 24 h.
(c) Cell proliferation detected by real-time cell analysis system (RTCA). (d) Immunofluorescent
images of tFNAs-treated chondrocytes (cytoskeleton: green, nucleus: blue, collagen II: red).
(e) Effect of tFNAs concentration on chondrocyte migration at 24 h, as determined by the wound
healing assay. (f ) Immunofluorescent images of tFNAs-treated chondrocytes (LC3: green, nucleus:
blue, actin: red). Source: Sirong et al. [68]/Springer Nature/CC by 4.0 (a); Reproduced from Shao
et al. [61], © 2017/John Wiley & Sons (b–d); Shi et al. [45], © 2017/John Wiley & Sons (e); Shi et al.
[69], © 2018/Royal Society of Chemistry (f ).
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10.5 Nucleic Acid Nanomaterial-Based Therapy for OA 187
Survival related pathway
Viability related pathway
ProliferationPhenotypeMigrationAutophagy Apoptosis
Collagen II
β-catenin
Lef-1
Cyclin D
Hes1
RhoANrf2
Bcl-2PI3K
ROCK2
Vinculin
Casepase-3
BeclinATG
LC3
mTOR
HO-1
Bax
AKT
Oxidative
stress
Aggrecan
GSK
Figure 10.3 tFNAs regulate intracellular signaling pathways in chondrocytes. Source: Drawn by
Figdraw.
10.5.1.2 Antisense Oligonucleotides (ASOs)
ASOs are composed of 15–30 nucleotides. They can bind to cell surface proteins and enter
cells by endocytosis [75, 76]. After binding to the target mRNA, ASOs form an RNA-DNA
hybridization and become a substrate of RNaseH, leading to RNA degradation and disrup-
tion of mRNA expression [77]. In exploring the pathogenesis of OA, it was found that after
treating chondroblasts and chondrocytes with ASOs against miR-9, caspase-3 activity and
the number of dead cells increased. The application of a miR-9 precursor was able to restore
the inhibitory eect of protogenin (PRTG) on cartilage dierentiation. These data suggest
that miR-9 can inhibit sulfated proteoglycan accumulation and cartilage nodule formation
by targeting PRTG and promoting cartilage dierentiation [78]. Locked nucleic acid (LNA)
technology is an improvement for ASOs. The ribose ring in the backbone is connected by
a methylene bridge between the 2
′
-O and 4
′
atoms, which signicantly increases binding
to the target RNA [79]. Local injection is a better method for OA delivery. It was discov-
ered that miR-181a-5p could be blocked by intra-articular injection of LNA-miR-181a-5p,
decreasing the expression of cartilage degradation genes and cell death markers [80]. More-
over, trauma-induced knee OA was alleviated in this manner. Baek et al. also discovered
that LNA-miR-449a ASOs targeting LEF1 and SIRT1 could regenerate damaged cartilage
and prevent the progression of OA [81].
10.5.1.3 Aptamers
Aptamers can not only be used as targeting vectors but have also been shown to regulate
gene expression. Aptamers have certain application advantages. Due to the small size of
DNA ligands, they are easily excreted from the blood. At the same time, they can be easily
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188 10 Framework Nucleic Acid Nanomaterial-Based Therapy for Osteoarthritis: Progress and Prospects
synthesized, chemically modied, and not immunogenic [81]. IL-17RA plays a central role
in the inammatory response. IL-17/ IL-17RA-mediated signal transduction is required for
the expression of IL-1, IL-6, and IL-8 [82, 83]. Chen obtained DNA aptamers designated
RA10-6, which could eectively block the binding of IL-17 to IL-17RA. When injected
into OA mice, synovial thickening was inhibited, and the concentration of IL-6 in synovial
tissue was reduced. Even more eective results were obtained by the combined use of cele-
coxib [84].
10.5.2 Vector-Dependent Nucleic Acid Nanomaterials for OA Therapy
miRNA, RNA mimics, siRNA, cDNA, mRNA, and circle RNA (CircRNA) are vector-
dependent nucleic acid nanomaterials [77]. They must be transported into cells by vectors
to play a role in gene regulation. Adenovirus, adeno-associated virus (AAV), herpes simplex
virus, retrovirus, lentivirus, and liposome are widely used viral vectors for nucleic acid
transfer [85]. In this part, the principle and related research on these nucleic acids are
presented. For the convenience of the readers, we have listed the relevant research works
in the last ve years in Table 10.2.
10.5.2.1 MicroRNA (miRNA) Mimics
miRNA is a single-stranded RNA consisting of 20–24 nucleotides. It belongs to a class of
non-coding RNAs. In most cases, miRNA pairs with the 3
′
-noncoding region of the tar-
get mRNA, blocking gene translation [126, 127]. It has been widely studied that miRNA
regulates autophagy, apoptosis, inammation, and cartilage degradation in OA [128–130].
Therefore, various miRNA mimics have been developed for the treatment of OA. Liang
encapsulated miR-140 mimics with chondrocyte anity peptide (CAP) exosomesand intro-
duced them into chondrocytes, which inhibited the expression of MMP-13 and ADAMT-5.
The increased miR-140 decreased the expression of MMP-13 and ADAMT-5 in rat OA model
and alleviated the cartilage damage [107]. Liang et al. stimulated human synovial broblasts
with IL-1β and then treated them with miR-26a-5p mimic-bearing exosomes. In vitro, apop-
tosis of synovial broblasts was observed. In addition, synovial hyperplasia was alleviated
in OA rats. In addition, inammatory cells and serum IL-1β were reduced [131].
10.5.2.2 Small Interfering RNA (siRNA)
siRNA is an articially produced double-stranded RNA. It consists of about 20 base pairs
and switches o various genes. During RNA interference, silencing protein complexes bind
to siRNA and form an RNA-induced silencing complex that cleaves the complementary
mRNA transcript, resulting in gene repression [132]. 15- LO -1 in primary chondrocytes was
silenced by si-15-LO-1, which signicantly reduced the secretion of cartilage extracellular
matrix, cartilage degrading enzymes, and the production of reactive oxygen species induced
by mechanical stress [133]. As reported by Xu et al., si-SOX11-1 was added to the human
chondrocyte line CHON -001 using Lipofectamine 2000. Knockout of SOX11 reduced the
expression of MMP-13 and caspase-3, increased the expression of collagen II, and inhibited
cell apoptosis [134]. In addition, Li et al. encapsulated Lipofectamine 2000 with si-XIST
and transfected it onto M1 macrophages, which inhibited the XIST/miR-376c-5p/OPN
axis and the inammatory markers secreted by M1 macrophages IL-1β, IL-6, and TNF-α.
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Table 10.2 Vector-dependent nucleic acid nanomaterials for OA therapy in recent five years.
Nucleic acid Gene/target Vector Cell used Animal used Ref
miRNA mimics miR-103a-3p Lipofectamine 2000 LPS-induced OA rat chondrocytes — [86]
miRNA mimics miR-24 Lipofectamine 2000 OA rat chondrocytes — [87]
miRNA mimics miR-146a PmirGLO OA patients’ chondrocytes — [88]
miRNA mimics miR-26a — — OA rat [89]
miRNA mimics miR-30a Lentivirus Rat bone marrow cells — [90]
miRNA mimics miR-93 PcDNA3.1 eukaryotic expression
vector
Primary mouse articular
chondrocytes
OA mice [91]
miRNA mimics miR-197 PcDNA3.1-EIF4G2 Human OA cartilage chondrocytes — [92]
miRNA mimics miR-21-5p Lipofectamine 2000 Primary mouse condylar
chondrocytes
SPF-grade white egg [93]
miRNA mimics miR-145 Not mentioned OA mice’s primary chondrocytes — [94]
miRNA mimics miR-146a-5p PmirGLO vector IL-1β-induced human and mouse
chondrocytes
OA rat [95]
miRNA mimics miR-204-5p Lipofectamine 2000 Human osteoarthritic synovial
broblasts
— [96]
miRNA mimics miR- 467b Lipofectamine 2000 LPS-induced mouse chondrogenic
ATDC5 cells
OA rat [97]
miRNA mimics miR-520d-5p Lipofectamine 3000 Human mesenchymal stem
cells/human OA chondrocytes
— [98]
miRNA mimics miR-590-5p Lipofectamine 3000 IL-1β-induced human chondrocytes — [99]
miRNA mimics miR-877-5p Lipofectamine 2000 IL-1β-treated primary mouse
chondrocytes
OA mice [100]
miRNA mimics miR-101 Lipofectamine RNAiMAX Rat mesenchymal stem cells — [101]
(Continued)
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Table 10.2 (Continued)
Nucleic acid Gene/target Vector Cell used Animal used Ref
miRNA mimics miR-411 Lipofectamine 3000 IL-1β-induced human chondrocyte
C28/I2 line
— [102]
miRNA mimics miR-140-5p RiboFECTTM CP transfection kit IL-1β-induced primary mice
chondrocytes
— [103]
miRNA mimics miR-135b Lipofectamine 2000 Synovial macrophages — [104]
miRNA mimics miR-140-5p Lipofectamine 2000 Synovial cells OA rat [105]
miRNA mimics miR-27a PcDNA3.1 — OA rat [106]
miRNA mimics miR-140 Exosomes IL-1β-induced human primary
chondrocytes
OA rat [107]
miRNA mimics miR-122 Lipofectamine IL-1β-induced rat primary
chondrocytes
— [108]
siRNA Notch1
siRNA
PLGA-PEG encapsulate
NO-HB@siRNA
Macrophages OA mice [109]
siRNA MMP-13 siRNA PLGA based microplates Murine chondrogenic cells (ATDC5) OA mice [110]
siRNA MMP-13& Adamts5
miRNA
not mentioned — OA mice [111]
siRNA YAP siRNA Lipofectamine 2000 IL-1β-induced mice primary
chondrocytes
OA mice [112]
siRNA MMP-13 siRNA not used — OA mice [113]
siRNA IκBζ siRNA Lipofectamine IL-1β-induced mouse chondrocytes — [114]
siRNA SGK1 Lipofectamine IL-1β-induced human chondrocytes — [115]
siRNA SGK1 Lipofectamine 2000 OA mouse chondrocytes — [116]
siRNA SOX11 Lipofectamine 2000 IL-1β-induced human chondrocytes
CHON-001
— [117]
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