The Therapeutic Potential of Targeted Nanoparticulate Systems to Treat Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a widespread autoimmune inflammatory disease. It implicates damage to bones, cartilage, and joints with uncertain pathogenesis. It is coupled with an elevated risk of cardiovascular complications and human disability. The conventional dosage forms for RA treatment pose numerous problems including poor efficacy, large dosages, frequent administration, limited responsiveness, greater expenses, and severe side effects. The nanoparticulate systems are emerging as a new thought for the diagnosis and treatment of RA. Anti-inflammatory drug-loaded nanoparticulate systems aid in the active and passive targeting of the inflamed region. Improved bioavailability and targetability are achieved by using these systems. In this review, the pathophysiology of RA and its conventional treatment has been discussed. The role of various nanoparticulate systems for passive and active targeting of RA has been reviewed. The authors have summarized the current practices in the typical and novel nanosystems to improve the quality of life in RA patients.

Full text

Review Article
The Therapeutic Potential of Targeted Nanoparticulate
Systems to Treat Rheumatoid Arthritis
Wenqing Liang ,
1
Yijun Yu,
2
Zunyong Liu,
1
Wenyi Ming,
1
Hongming Lin,
1
Hengguo Long ,
1
and Jiayi Zhao
1
1
Department of Orthopaedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese
Medical University, Zhoushan 316000, China
2
Medical Research Center, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University,
Zhoushan 316000, China
Correspondence should be addressed to Wenqing Liang; liangwq@usx.edu.cn, Hengguo Long; longhgzs@163.com,
and Jiayi Zhao; zjy2038689@sina.com
Received 6 July 2022; Revised 13 August 2022; Accepted 30 August 2022; Published 12 October 2022
Academic Editor: Abdelwahab Omri
Copyright © 2022 Wenqing Liang et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Rheumatoid arthritis (RA) is a widespread autoimmune inflammatory disease. It implicates damage to bones, cartilage, and joints
with uncertain pathogenesis. It is coupled with an elevated risk of cardiovascular complications and human disability. The
conventional dosage forms for RA treatment pose numerous problems including poor efficacy, large dosages, frequent
administration, limited responsiveness, greater expenses, and severe side effects. The nanoparticulate systems are emerging as a
new thought for the diagnosis and treatment of RA. Anti-inflammatory drug-loaded nanoparticulate systems aid in the active
and passive targeting of the inflamed region. Improved bioavailability and targetability are achieved by using these systems. In
this review, the pathophysiology of RA and its conventional treatment has been discussed. The role of various nanoparticulate
systems for passive and active targeting of RA has been reviewed. The authors have summarized the current practices in the
typical and novel nanosystems to improve the quality of life in RA patients.
1. Introduction
Arthritis is characterized as the inflammation of one or more
joints [1]. There are several signs and symptoms of the dis-
ease that include redness of the joints, swelling of the joint
and joint discomfort, and joint warmth [2]. Rheumatoid
arthritis (RA) and osteoarthritis (OA) are the most frequent
forms of arthritis. OA is caused by mechanical wear and tear
on joints while RA is classified as an autoimmune disorder
[3, 4]. RA tends to impact numerous joints of the body. If
left untreated, RA damages bone and cartilage, which makes
it difficult for patients to do daily tasks like working or going
to social gatherings. This condition is called chronic RA [5].
Figure 1 represents the manifestation of types of arthritis
joints. When the tendon is inflamed (tenosynovitis), it
results in both the loss of cartilage and the erosion of bone
[6]. RA has a heterogeneous clinical response to the different
treatments [7]. RA affects around 5 out of every 1000 people
and tragically, 80 percent of those affected face disability
within 20 years after the early symptoms.
There are several antiarthritic medications on the market
today and most of them are relatively expensive, have limited
efficacy, and/or have unavoidable adverse effects. Inflamma-
tory drugs are one of the most expensive treatment categories
for health care [9]. Nonsteroidal anti-inflammatory drugs
(NSAIDs), glucocorticoids (GCs), disease-modifying anti-
rheumatic drugs (DMARDs), and biological agents are
widely prescribed to treat RA. NSAID-induced nephrotoxic-
ity, liver damage, and heart failure are all potential side effects
of these treatments, despite their ability to slow the progres-
sion of the disease [10, 11]. If medication continues to be
ineffective, the only other option is surgery [12–14].
An effective alternative to these outdated therapeutic
procedures is required. This review has been focused on
Hindawi
Journal of Nanomaterials
Volume 2022, Article ID 8900658, 15 pages
https://doi.org/10.1155/2022/8900658

novel strategies to treat RA. The role of nanotechnology-
based nanoparticulate systems will be discussed. The
lipid, polymer, metal, inorganic nonmetal, and bionic
technology-based nanoparticulate systems will be elaborated.
Current progress in different nanodrug delivery systems to
treat RA will also be highlighted.
2. Role of Nanoparticulate Systems in
RA Treatment
Nanotechnology has revolutionized every field of applied
science. Nanoparticulate systems have attracted attention
for their potential to explore a variety of anti-inflammatory
drug-loaded nano formulations [15]. Table 1 includes some
of the nanoparticulate systems reported for the treatment
of RA.
Many researchers have been working on the develop-
ment of various nanoparticulate systems for treating RA by
either directly or indirectly targeting the area of inflamma-
tion. Improved bioavailability, targetability, and enhanced
therapeutic action are the main advantages of these systems.
Prolonged circulation time is achieved by pegylated nano-
particulate systems. Additionally, smart nanoparticulate
systems have been designed that release the therapeutic
agent only when a trigger or stimulation is encountered.
The graphical representation of such systems has been rep-
resented in Figure 2. Mahtab et al. discovered the enhanced
permeability and retention (EPR) effect that provided a
crucial push intended for extensive research into the
application of nanoparticulate systems. Passive targeting
mainly depends on the EPR effect. Angiogenesis (newly
created blood vessels) is critical in chronic inflammatory
diseases like RA because of local hypoxia and growth factor
generation at inflamed joints. Active targeting following
systemic delivery can be accomplished by coating nanopar-
ticulate systems with a targeting moiety. As the disease
progresses, angiogenesis and inflammation are the most
prominent features. Growth factors, cytokines, adhesion
molecules, and proteases have all been implicated in the
formation of angiogenesis in various ways. The vascular
endothelial growth factor (VEGF) and angiopoietin play a
key function in the hypoxia-VEGF system. The endothelial
cell surface is also overexpressed with many adhesion mole-
cules, including integrin v3, E-selectin, vascular cell adhesion
molecule-1 (VCAM-1), and intercellular cell adhesion
molecule-1. Inflamed synovial membranes are rich in mac-
rophages, which have a wide range of proinflammatory
properties and contribute significantly to inflammation and
joint damage. The selective delivery of nanomedicine by
binding to a specific receptor could switch offtheir compli-
cated connections with other cells and improve the condi-
tion of RA while preserving the basic functions of resting
macrophages. CD44, CD64, folate receptor-beta (FR-), vaso-
active intestinal peptide (VIP) receptor, scavenger receptor
class A, toll-like receptors, transforming growth factor-beta
receptors, etc. were observed to be over-expressed on acti-
vated macrophages [31]. The antibodies or other specialized
adhesion molecules (e.g., selectins) are bound to the surface
of nanoparticulate systems [32]. Redox-responsive clustered
Fe
3
O
4
nanoparticles (NPs) were produced in a study. Fe
3
O
4
-
based nanoclusters (NCs) of these NPs were produced
following laser irradiation to exhibit adjustable r1 and r2
relativities, thereby enabling enhanced dual-mode T1/T2-
weighted MR imaging of inflammatory arthritis [33].
3. Synthetic Nanoparticulate Systems
Based on the particle integrity, the synthetic nanoparticulate
systems can be categorized into two major categories: the
nonrigid nanoparticles, which include liposomes and solid
Healthy synovial joint Rheumatoid arthritis
Redox imbalance
Inammation
Compact bone
Spongy bone
Articular cartilage
Synovial membrane
Synovial uid
Synovial oxidative stress
Cartilage damage
Pannus
Joint cavity
(contains synovial uid)
Figure 1: Normal joint vs RA joint. Reproduced from [8].
2 Journal of Nanomaterials

Table 1: Nanoparticulate systems for the treatment of RA.
Nanoparticulate system Drug In vivo model Outcome Ref
Liposome
(nonrigid nanoparticulate system) Dexamethasone Rats with adjuvant-induced arthritis
Significantly down-regulated serum
proinflammatory cytokines including tumor
necrosis factor-αand interleukin-1βwhen compared
to free dexamethasone
[16]
Liposome/gold nanoparticles
(hybrid nanoparticulate system) Ubiquinone Mice with collagen-induced arthritis Proinflammatory cytokines were
significantly decreased [17]
Calcium phosphate/liposome-based
nanocarrier (hybrid nanoparticulate system)
siRNA and
methotrexate (MTX) Mice model Blocked the transcription factor NF-kB and reduced
the expression of proinflammatory cytokines [18]
Solid lipid nanoparticles
(nonrigid nanoparticulate system) β-Sitosterol
Complete Fruend adjuvant (CFA)-
induced arthritis via a dual pathway
in rats
Increased the redox status of synovium {reduced the
malonaldehyde (MDA) and increase superoxide
dismutase (SOD), glutathione (GSH), and catalase
(CAT)} levels, and reduced the cytokines such as
tumor necrosis factor-α(TNF-α), interleukin-1β(IL-
1β), IL-2, 6, 16, and 17 and increased level of IL-10,
transforming growth factor beta (TGF-β). Reduced
the level of cyclooxygenase-2 (COX-2), prostaglandin
E2 (PGE2), vascular endothelial growth factor
(VEGF), and NF-κB.
[19]
Chitosan-coated solid lipid nanoparticles
(hybrid nanoparticulate system) Leflunomide Rats with adjuvant-induced arthritis Improved joint healing and reduced hepatotoxicity [20]
Chitosan and hyaluronic acid-based polymeric
nanoparticles (rigid nanoparticulate system) Antibodies Biological assays Selectively captured and inactivated the
proinflammatory cytokine IL-6 [21]
Ethyl cellulose and Eudragit S-100-based polymeric
nanoparticles (rigid nanoparticulate system) Mefenamic acid In vitro drug release Greater stability and controlled drug release for 12 h. [22]
Poly(lactic-co-glycolic acid) (PLGA)–PEG–folic acid
(FA), sodium deoxycholate (SDC), and solutol HS15
(HS15) nanocarriers (rigid nanoparticulate system)
Germacrone Adjuvant-induced arthritis
(AIA) rats
Levels of proinflammatory cytokines
(TNF-α, IL-1β) in the rat’sinflammatory tissue were
significantly reduced
[23]
Polyethylene-glycol (PEG)-fabricated multiwalled
carbon nanotubes (rigid nanoparticulate system)
Corticosteroids
(triamcinolone) Biological assays Significantly inhibited the inflammatory response of
fibroblast-like synoviocytes [24]
Single-walled carbon nanotubes
(rigid nanoparticulate system) Targeted carrier K/BxN serum transfer (STA) model Specifically targeted cells homing to or present in
arthritic joints [25]
Hyaluronate–gold nanoparticle/tocilizumab
(HA-AuNP/TCZ) complex (rigid
nanoparticulate system)
Tocilizumab
(monoclonal antibody)
Collagen-induced arthritis (CIA)
model mice by ELISA
Reduced levels of inflammatory cell infiltration and
cartilage and bone destruction [26]
Multifunctional dendrimer-entrapped gold
nanoparticles (rigid nanoparticulate system)
Codelivery of antioxidant
alpha-tocopheryl succinate
(α-TOS) and
anti-inflammatory
anti-TNF-αsiRNA
CIA mouse model
Better antioxidative effect and the most significant
decrease of mRNA of TNF-αand TNF-αprotein in
the ankle joints
[27]
3Journal of Nanomaterials

Table 1: Continued.
Nanoparticulate system Drug In vivo model Outcome Ref
Folate/RGD-dual-functionalized mesoporous silica
nanoparticles (rigid nanoparticulate system) Polydatin CIA model Joint damages were significantly improved [28]
Biomimetic exosome (bionic)
Glucocorticoids
(dexamethasone sodium
phosphate (Dex) nanoparticle
(Exo/Dex))
In vitro study and CIA mice
Enhanced endocytosis and excellent anti-
inflammation effect against RAW264.7 cells and
in vivo model significantly reduced inflamed joints
[29]
Metabolically engineered exosomes (bionic) Engineered exosomes as a
next generation drug for RA CIA mice model
Promoted M1-M2 macrophage polarization in the
bone marrow regions of joints inflamed by RA and
reduced the activity of surrounding proinflammatory
cells, such as M1 macrophages, activated synovial
fibroblasts, and TH17 cells
[30]
4 Journal of Nanomaterials

lipid nanoparticles, and the rigid nanoparticles, which
include polymeric nanoparticles and nanoparticles made of
inorganic materials.
3.1. Nonrigid Nanoparticulate Systems. It is well-known that
nonrigid nanoparticulate systems have relatively soft struc-
tures that are easily disrupted by an external force. The non-
rigid nanoparticulate systems include liposomes and solid
lipid nanoparticulate systems (SLNs). Nonrigid nanopartic-
ulate systems have an important role in the treatment of RA.
3.1.1. Liposomes. Liposomes are derived from the Greek
words “lipo”and “soma,”which mean “fat”and “body,”
respectively. Dr. Alec Bangham and Dr. Horne pioneered
the concept of liposomes in 1964. Liposomes are vesicles that
can hold hydrophilic (water-soluble) drugs, hydrophobic
drugs (water-insoluble), peptides, and nucleic acids effec-
tively. It is possible to compartmentalize a variety of drugs
in a single formulation using liposomes. Vesicles made up
of lipids and cholesterol are safe, nontoxic, noncarcinogenic,
nonthrombogenic, and biodegradable in the natural envi-
ronment [35].
The targeted delivery of various drugs can minimize
their side effects. Methotrexate (MTX) is a commonly pre-
scribed medication for the treatment of RA. MTX was
loaded with higher encapsulation efficiency in liposomes
(>30%). Experiments in arthritic animals demonstrate that
liposomes encapsulating MTX considerably boosted the
biological effect [36]. Similar results have been reported with
polymerized stealth liposomes as a delivery system for the
enhanced anti-inflammatory effect of dexamethasone for
the treatment of RA. It was shown that the polymerized
stealth liposomes remained stable in blood vessels for a sub-
stantial amount of time. Cells were able to metabolize these
without inflicting any serious damage. Upon injection into
arthritic rats, polymerized stealth liposomes with dexameth-
asone displayed prolonged circulation and accumulated
primarily in the affected joints. The in vivo animal study
confirmed suppressing of the proinflammatory cytokines
(TNF- and IL-1A) in joint tissues, thereby, decreasing joint
swelling, and slowing down the progression of RA [37]. In
another study, folate conjugated double liposomes contain-
ing prednisolone and MTX were used to target RA. The
folate receptor is well-known to be expressed at a higher
level in inflamed cells than in normal cells. Both drugs were
shown to have a larger concentration in inflamed joints than
in noninflamed joints [38]. The thermosensitive liposomes
can further enhance the targeted drug delivery. Sinomenine
hydrochloride (SIN-TSL) was loaded into a unique thermo-
sensitive liposome created using a pH gradient technique.
When the temperature was increased from 37 to 43
°
C, the
rate of drug release was significantly faster than at 37
°
C.
SIN-TSL with microwave hyperthermia increased anti-RA
effects in both in vitro and animal studies [39].
T-helper type-17 (Th17) cells are dramatically increased
by the proinflammatory cytokine interleukin-23 (IL-23) in
the conditions like RA. Biofunctionalized liposomes were
studied by Lima et al. to deliver anti-IL-23 antibodies
(Abs) effectively. Systemic administration of Abs is limited
by the risk of significant side effects and the short half-life
of these Abs. A liposomal immobilization technique was
used to improve the therapeutic efficacy of anti-IL-23 Abs.
Because of the anti-inflammatory and antioxidant capabili-
ties, gold nanoparticulate systems (AuNPs) were loaded into
Active targeting
Passive targeting
Internal stimuli
Synovial broblast Synoviocyte
Plasma cell
Vascular endothelial cell
Dendritic cell
Macrophage T cell
Osteoclast Mast cell
B cell
External stimuli
Folate receptor
NIR
Magnetic eld
CD 44
. . .
𝛼v𝛽3-integrin
EPR eect
PEGylation
Energy induced
Low pH
Enzymes
Temperature
Figure 2: Passive targeting, active targeting, and stimuli-responsive nanoparticulate systems for RA treatment. Reproduced with permission
from [34].
5Journal of Nanomaterials

the liposomes. Tests on human articular chondrocytes, mac-
rophages, and endothelial cells showed their hemocompat-
ibility and cytocompatibility. These liposomes significantly
reduced the synthesis of IL-17A by peripheral blood mono-
nuclear cells from healthy donors and RA patients who had
been driven to Th17 differentiation [40]. Gouveia et al.
reported a synovial cell-targeted drug delivery approach
using hyaluronic acid (HA) conjugated pH-sensitive
liposomes. The CD44 is overexpressed in synovial cells
and HA has a high affinity for CD44. The caveolae- and
clathrin-dependent endocytosis enables the selective uptake
of lipids. The acidic environment caused the breakdown of
these pH-sensitive liposomes. Prednisolone was released into
the cytosol through intracellular compartments in a regu-
lated manner, minimizing the off-target distribution of the
drug. It was found that combining these two approaches
(HA and pH) boosted prednisolone’s bioavailability and
improved its focused therapeutic efficiency while decreasing
its well-known adverse effects [41]. Fibroblast-like synovio-
cytes (FLS) have been identified as a major contributor to
RA etiology by numerous studies. FLS increases the progres-
sion of RA by producing tumor-like growth and the produc-
tion of pannus in the joints. Berberine (BBR) has recently
been discovered to be a powerful activator of miR-23a, which
results in downstream suppression of inflammatory kinases
such as ASK1 and GSK-3 in RA disease. Drug-loaded nano-
particulate systems including herbal bioactive substances like
berberine have also been developed. PEGylated liposomal
berberine and PEGylated liposomal miR-23a were used as
therapeutic targeting of an adjuvant-induced arthritic disease
model. In the study, raised anti-inflammatory action was
achieved. The liposomal formulations employed in this study
increased the drug’s steady-state distribution, resulting in
anti-inflammatory activity, decreased pannus development,
decreased cartilage deterioration, and decreased bone ero-
sion. BBR absorption suppressed the Wnt1/-catenin pathway
by altering several parameters associated with the clinical
complication of rheumatoid arthritis disease, potentially via
increasing miR-23a levels [42].
3.1.2. SLNs. There has been an enormous amount of atten-
tion paid to SLNs since their introduction in 1991, and they
have been used as a highly effective method of delivering
medications and DNA and targeting therapies [43]. SLNs
are made of a solid lipid core, such as triglyceride or stearic
acid, as well as waxes and emulsifiers. Numerous methods
were studied for the preparation of SLNs, e.g., solvent emul-
sification/evaporation approach [44, 45]. SLNs may have an
edge over other types of nanoparticulate systems because of
their high biocompatibility, increased drug loading capacity,
and scalability. The drawbacks of the conventional nanocar-
riers include polymer degradation and cytotoxicity; lack of
suitable large-scale production process; insufficient stability;
drug leakage and fusion; phospholipid degradation; high
production cost; and sterilization problems. The high-
melting fat matrix-based SLNs are being developed to
overcome the limitations of conventional colloidal carriers
including liposomes and polymeric nanoparticulate systems
[46]. Figure 3 represents the difference between the lipo-
somes and the SLNs and the advantages of the SLNs.
Colloidal drug delivery technologies such as SLNs have been
shown to improve drug entrapment, bioavailability, and
pharmacokinetic characteristics of hydrophilic and hydro-
phobic drugs [47].
The targeted drug delivery with minimal burst release
has been achieved with the SLNs [43, 48]. Piperine-loaded
SLN dispersion to maximize its oral and topical effectiveness
was reported. The prepared SLN was given orally and topi-
cally to rats with CFA-induced arthritis. Piperine from the
SLN gel formulation accumulated in the skin, according to
ex vivo results utilizing the Franz diffusion cell. The pharma-
codynamic study results revealed that both topical and oral
piperine elicited a substantial response when compared to
chloroquine suspension administered orally [49]. The FDA
has approved leflunomide (LEF) for use in the treatment of
RA. However, a wide range of gastrointestinal side effects,
including nausea, diarrhea, vomiting, and stomatitis have
been attributed to oral LEF treatment. After the application
of chitosan (CS) on the surface of the SLNs, folic acid was
added (FA). As compared to oral LEF suspension in rats
with adjuvant-induced arthritis (AIA), the oral treatment
of FA-CS-SLNs resulted in increased joint healing and
decreased hepatotoxicity [20].
The SLNs provide oral as well as topical drug delivery.
Piroxicam is an effective anti-inflammatory, antipyretic,
and analgesic medication; nevertheless, its oral administra-
tion for extended periods is limited due to a variety of gas-
trointestinal adverse effects. SLNs containing piroxicam
were prepared using the solvent emulsification/evaporation
process. Using guinea pig skin placed on a modified Franz
diffusion cell, the in vitro penetration of piroxicam through
the SLN-based nanoparticulate system was evaluated. SLN
formulations showed improved skin permeability [50].
Curcumin (CUR) is a natural product that has anti-
inflammatory properties. Jeevana and Muni developed SLNs
to increase the solubility of CUR. The CUR content of SLNs
Surfactant layer
Solid lipid core
Hydrophilic (Aq.) part
Hydrophobic part
SLN are
More stable
Provide high EE%
Provide high DLE%
Nontoxic and biodegradable
Easy to formulate at large scale
Figure 3: Schematic presentation of the complete structure of solid lipid nanoparticulate systems with advantages over liposomes.
6 Journal of Nanomaterials

was reported to be 98.7-99.3%. These results indicated
minimal CUR loss during the SLN production process. Ex
vivo tests on goat skin showed that SLN topical gel released
a significant amount of CUR (76.93%) within 30 minutes of
being applied to the skin membrane. Similarly, in the in vivo
application, an X-ray radiographic study of untreated rats
revealed abnormalities in the hind paws. The treatment with
CUR-SLNs prevented these deformities and significantly
reduced paw edema in the treated rats [51].
3.2. Rigid Nanoparticulate Systems. Rigid nanoparticles have
been shown to have a higher mechanical strength than non-
rigid lipid-based nanoparticles published thus far. Rigid
nanoparticles are classified into these key subcategories: bio-
degradable polymeric nanoparticles, carbon nanotubes, and
metallic and inorganic nanoparticles.
3.2.1. Polymeric Nanoparticulate (PNP). Solid nanoparticu-
late, core-shell structures, polymeric micelles, and polyplexes
are all examples of biodegradable PNP formulations. Nano-
particulate formulation and synthesis methods are depen-
dent on the polymer and cargo characteristics; however,
PNP is most often generated via self-assembly or emulsion
in most cases. PNP Polymers may be assembled in a variety
of ways, including the formation of complexes of cationic
polymers with anionic nucleic acids, as well as the sponta-
neous formation of micelles when the concentration of
amphiphilic block copolymers reaches a threshold micelle
concentration. Nanoparticulate may also be created by
procedures such as emulsification, in which droplets of
one phase are disseminated in another. Solubilized in an
organic phase, polymers are often combined with surfac-
tants and ultrasonicated at high power in an aqueous solu-
tion to produce nanodroplets [52]. Hardened polymer
nanoparticles are formed when the solvent evaporates
from the emulsion. They may also be encased in another
material to create core-shell nanoparticulate with desirable
surface features [53]. PNP is divided into two main catego-
ries: Polysaccharides and proteins produced from natural
sources. Peptides and polysaccharides may be degraded in
the body using enzymes and the breakdown rate can be
controlled to get the desired release profile. Dextran, gelatin,
poly(L-lysine), chitosan, and alginate are among them
[21, 54]. The delivery channels and disease targets may
all benefit from synthetic polymers that have desired features
such as hydrophobicity and degradation profile. Poly(Lac-
tide-co-Glycolide), poly(-caprolactone), sugar cyclodextrins,
and poly(-amino ester) are examples of these polyesters [55].
There are a variety of ways to deliver drugs for the treat-
ment of RA. Targeted drug administration based on stimuli
is the most prevalent method. Stimuli from the micro- or
macroenvironment can alter the physical properties of
stimulus-sensitive polymers [56]. Polymer transitions are
influenced by factors such as solubility, hydrophilic/lipo-
philic balance, solvent interactions, and conductivity. These
changes are driven by chemical reactions including acid-
base interaction, redox, thermal, or hydrolysis of compounds
linked to the polymer chain [57].
pH shift has been used to cause the release of integrated
therapeutics whenever environmental changes are related to
pathophysiological processes such as inflammation [58]. In
this context, the idea of using pH-sensitive PNP-carrying
therapeutic compounds (NSAIDs, GCs) in RA treatment
has great potential. The enhanced angiogenesis that occurs
in RA leads to the discontinuity of inflammatory endothe-
lium cells and an increase in vascular permeability. This
abnormality may allow nanosystems of the appropriate
size to successfully enter inflamed joints [59]. Following
enhanced delivery of anti-RA drugs via nanoparticulate
systems, low pH vicinity causes the drug to be delivered
directly into the affected area of the body. Using this
approach, it is possible to increase the efficacy of RA ther-
apeutics by increasing therapeutic selectivity and reducing
systemic side effects. Dexamethasone- (DEX-) loaded
HAPNPs (HA-coated acid-sensitive PNPs) were examined
by Yu et al., for the treatment of RA. PCADK, a polyketide
with a high degree of acid sensitivity, was used to make the
acid-sensitive polymeric material that comprised egg phos-
phatidylcholine, polyethyleneimine, and PCADK. As a result
of its ability to bind CD44, HA was chosen as a targeting moi-
ety. An average diameter of 150.5 nm was shown to have a
pH-dependent drug release characteristic in the nanoparticu-
late system. HAPNPs demonstrated a strong ability to target
activated macrophages because of the presence of HA on the
nanoparticulate systems, as demonstrated by cellular uptake
experiments. It was also shown that HAPNPs/DEX treat-
ment reduced inflammatory cell infiltration, bone degrada-
tion, and cartilage damage in the ankle joints of rat models
of AIA [60].
The phase-transition behavior of temperature-responsive
polymers is considered while selecting these materials. Poly-
mers with a lower critical solution temperature (LCST) for
whom the solubility is influenced by temperature changes
are widely used to develop nanocarriers with thermo-
responsive properties. Transitional polymers become more
soluble, and their components swell due to hydrogen interac-
tions between water molecules and the polymer functional
groups. This property makes these polymers suitable for
loading drugs below the LCST. During the shift from hydro-
philic to hydrophobic, a morphological change occurs from
the coil to the globule, due to a change in the temperature.
During this transition, the hydrogen bonds and network col-
lapse, resulting in the polymer being insoluble and the water
molecules being squeezed out of the polymer. The guest drug
molecules are released because of this transformation.
Figure 4 depicts the mechanism of action of thermo-
responsive drug delivery systems [61].
Drug administration via photo-responsive polymers is
based on their ability to absorb light. Upon exposure to light,
these polymers change phase. The moieties are responsive to
UV, visible, and near-infrared light. These materials are
appealing because of their water solubility, biodegradability,
and biocompatibility, as well as their ability to manage the
spatial and temporal triggering of drug release. Two basic
tactics may be utilized depending on the application: one
time or repeated on-offactive compound release. This is
plausible because some materials, when exposed to light,
7Journal of Nanomaterials

can undergo irreversible structural changes, while others
when the trigger is removed, can return to their former state
[62]. Fomina et al. used a self-immolating quinone-methide
system to create degradable nanoparticulate systems made of
photo-sensitive polymers. The new photo-sensitive nano
system initiated the release of tiny hydrophobic compounds
in a controlled burst. As a result of the system’s adaptable
architecture, the triggering group was responsive to both
internal and external stimuli, which offered a lot of promise
for RA therapy. Authors of another study described a poly-
meric substance that was exposed to two-photon absorption,
and disassembled in response to near-infrared irradiation,
at biologically tolerable levels. Many pendants’protective
4-bromo7-hydroxycoumarin groups were photolyzed, start-
ing a chain reaction that finally destroyed the polymer’s
backbone by cyclization and rearrangement [63].
Redox-sensitive nanoparticulate systems are another
area of interest in the search for new ways to deliver drugs.
People’s interest in this type of system has been sparked by
the redox potential difference between the oxidizing and
reducing compartments. Reactive oxygen species (ROS)
have a critical role in the pathophysiology of chronic inflam-
matory arthropathies like RA. ROS are created mostly
during oxidative phosphorylation, although they may also
be formed during an oxidative burst by activated phagocytic
cells. They act as a key intracellular signal that boosts the
inflammatory response [8]. Pu et al. reported chitosan-
based nanoparticles with dual responses to oxidative stress
and reduced pH for curcumin release and its anti-
inflammatory applications. This occurred because curcumin
and the carrier had Förster resonance energy transfer. It also
allowed us to keep tabs on how the intracellular release was
progressing. Upon activation, curcumin might effectively
neutralize excess oxidants generated by macrophages that
had been activated with lipopolysaccharide (LPS). The
anti-inflammatory properties of curcumin-loaded nanopar-
ticles were tested on LPS-induced ankle inflammation in a
mouse model [64].
3.2.2. Carbon Nanotubes and Nanohorns. Carbon nanotubes
(CNTs) are made up of sheets of six-membered carbon atom
rings that have been folded into cylinders. Single-walled
carbon nanotubes (SWCNTs) have just one layer, whereas
multiwalled carbon nanotubes (MWCNTs) have two or
more layers (MWCNTs). CNTs are also known as cup-
stacked carbon nanotubes and carbon nanohorns [65].
These enticing carbon nanostructures are now being used
in a variety of medication delivery methods for the treatment
of life-threatening disorders. CNTs have been used to treat
inflammatory illnesses like RA, according to many studies.
Kayat et al. investigated the use of folate-anchored CNTs
to target an antiarthritis drug, (MTX), to the arthritic
inflammatory region. In comparison to naked MWCNTs
packed with MTX, as well as free MTX, folate-conjugated
MWCNTs significantly enhanced percentage inhibition of
RA, biological half-life, and MTX delivery rate. The recent
results show that drug-loaded functional MWCNTs may
change pharmacokinetics while also providing a steady and
optimal drug delivery mechanism [66].
A small interfering RNA (siRNA) targeting the
NOTCH1 gene was investigated as a therapeutic carrier for
MTX in HiPco- and carboxyl-SWCNTs made by Andersen
et al. MTX was covalently attached to the nanotubes after
they had been solubilized with PEGylation. A serum transfer
mouse model showed that SWCNTs mainly accumulated in
joints that were inflamed. They found that both SWCNTs
were related to B cells, monocytes, and neutrophils in the
blood. Adding MTX to SWCNTs reduced their ability to
target immune cells, particularly B cells; however, siRNA
alone boosted their ability to target immune cells. Targeting
specificity to neutrophils and monocytes was increased when
both MTX and siRNA were loaded into carboxyl-SWCNTs,
but not to B cells. It was possible to alter the targeting
specificity by changing the ratio of MTX and siRNA on
SWCNTs [67].
3.2.3. Metallic Nanoparticulate Systems. Metal nanoparticu-
late have outstanding characteristics, may have numerous
functional groups added to them, and are frequently
employed in biological applications [68]. Kim et al. devel-
oped manganese ferrite and ceria nanoparticle-anchored
mesoporous silica nanoparticles (MFC–MSNs) to cure
RA. Degenerative features were reduced in the CIA rat
model when MFC–MSNs were injected intra-articularly.
They have a synergistic effect on scavenging ROS and pro-
ducing O2, and they may reduce M1 macrophages while
polarising M2 macrophages. Furthermore, as a delivery
vehicle, monodisperse silica nanospheres may continuously
release MTX, enhancing the therapeutic impact as shown
in Figure 5 [69].
<LCST >LCST
Drug molecule
LCST
transition
Figure 4: Mechanism of action of thermo-responsive drug delivery system.
8 Journal of Nanomaterials

In another study, Kalashnikova et al. created albumin-
cerium oxide nanoparticulate that were indocyanine green
conjugated (ICG). The nanoparticulate systems were put
into the CIA mice’s swollen joints, and an in vivo imaging
system showed that they accumulated in the affected joints
and had a stronger therapeutic impact. This unique
albumin-cerium oxide nanoparticulate’targeting and thera-
peutic impact point us to a new route for arthritis therapy
[70]. Lee et al. created a hyaluronate–gold nanocarriers/toci-
lizumab (HA-AuNP/TCZ) as a combination therapy for RA.
In this treatment, AuNP was exploited as a therapeutic
carrier that reduced angiogenesis. TCZ is a monoclonal anti-
body that binds against the interleukin-6 (IL-6) receptor that
is exploited as an immunosuppressive treatment in the
initiation and progression of RA by interfering with IL-6.
HA is well-known for its cartilage-protecting and lubricating
qualities. End-group thiolated HA was synthesized by alter-
ing HA with cystamine by reductive amination, which was
then reduced with dithiothreitol (DTT) (HA-SH) (HA-
SH). HA-SH was utilized to chemically modify AuNP,
whereas TCZ was employed to physically modify it. In
collagen-induced arthritis, the therapeutic effect of the HA-
AuNP/TCZ combination on RA was verified [26].
3.2.4. Inorganic Non-metallic Nanomaterials. One of the
most often used RA drug delivery techniques is based on
injectable silica-based nanoparticulate systems. By using a
core–cone structure, Li et al. produced mesoporous silica
nanoparticulate systems (MSN-CC) as more convenient,
efficient, and long-lasting therapeutic than the previous
method of injecting HA. In a rat model of RA, this nanoma-
terial enhanced the synthesis of HA, reduced synovitis
inflammation, and promoted bone repair. Hyaluronan
synthase type 2 (HAS2) has high protein loading capacity
and good biocompatibility, degradation, and degradability.
Functionalized group PEI was applied to the surface of
mesoporous silica to load and deliver HAS2. Intra-articular
injection of MSN-CC-PEI successfully transported HAS2
into synovial cells and boosted the production of endoge-
nous HA both inside and outside the body [71]. Local percu-
taneous injection and nano-controlled MTX release were
studied by Guo et al. The MTX-mSiO2@PDA system was
highly responsive in terms of pH. After 24 hours, the cumu-
lative amount of MTX transferred from MTX-mSiO2@PDA
to pH 5.0 receptor fluid via the entire skin was nearly three
times larger than the amount transferred to pH 7.4 receptor
fluid in vitro local percutaneous injection studies. Further
in vivo testing in DBA/1 mice utilizing a CIA paradigm
found that the thickness of a mouse’s toes fell to roughly
65 percent of its initial level after 27 days of local percuta-
neous MTX-mSiO2@PDA injection. It was shown that the
toe thickness variation of mice administered with MTX-
Manganese
ferrite NPs
(MF)
Ceria NPs
(C)
Mesoporous
silica NPs
(MSNs) : ROS
Polarization Inammatory
cytokines
M1 M2
M1 macrophage
(inammatory)
M2 macrophage
(anti-inammatory)
Hypoxic
Rheumatoid
Arthritis joint
CMF
Synergistic
H2O2
O2
OH
Low O2
(Hypoxia) H2OO2
1
2
MFC-MSNs MTX-loaded
MFC-MSNs
MTX release
Tissue
damage
ROS
HIF-1𝛼
1) ROS
scavenging
2) O2
generation
O2 generation
PEG
Anti-rheumatic drug
methotrexate
(MTX)
+
Figure 5: Therapeutic mechanisms of MFC–MSNs in RA treatment. Reproduced with permission from Copyright (2019) American
Chemical Society [69].
9Journal of Nanomaterials

mSiO2@PDA through local percutaneous injection was
substantially lower than that of animals given MTX
directly [72].
4. Bionic Nanomaterials
Bionics is the study of biologically inspired engineering-
based materials and their applications [73]. The application
of bionics in nano drug delivery systems has revolutionized
the field of biomaterials. Despite successful PEGylation and
phospholipid modification, synthetic nanoparticulate sys-
tems that persist in living animals quickly elicit an immu-
nological response, followed by fast immune system
eradication. Thus, the application of bionics for the bio inter-
facing strategy to enable prolonged circulation time has
gained much importance. Cell membrane-coated and
exosomes-encapsulated nanoparticulate systems have found
a prominent place in novel drug delivery systems.
4.1. Cell Membrane-Based Nanoparticulate Systems. The
nanoparticulate systems have grown in popularity in recent
years, in part due to the similarity they have with real biolog-
ical systems. An endogenous cell membrane (e.g., macro-
phage) is used as a functional material on the surface of
the nanoparticulate systems to minimize immunogenicity
and extend blood circulation duration [74]. These systems
certainly inherit the antigenic surface and associated mem-
brane functions, such as chemotaxis to inflamed regions
and cytokine neutralization, from their source cells. Macro-
phages and neutrophils are important innate immune cells
in the human body. These cells are involved in the body’s
inflammatory response. These can cause synovial hyperpla-
sia i.e., the release of a variety of degrading enzymes, carti-
lage degradation, and the production of inflammatory
factors [75]. Immune cells are widely used to synthesize bio-
mimetic nano particulates with anti-inflammatory proper-
ties. Biohybrid delivery systems can be constructed using a
range of natural cells, including red blood cells, platelets,
immune cells, malignant cells, and even E. coli, as the mem-
brane source [76]. As a result, immune cells are frequently
employed to synthesize biomimetic nanoparticulate systems
with anti-inflammation characteristics. Recently, a variety of
natural cells, including red blood cells, platelets, immunolog-
ical cells, malignant cells, and even E. coli, have been pro-
duced [77]. The nanoparticulate systems described above
have also been reported with cell membrane coating to be
utilized as biomaterials. Figure 6 represents the application
of cell membranes to encapsulate the nanoparticles.
Macrophage cell membranes based on porous silicon
nanoparticulate systems (Psi) have been described as com-
posite platforms for the treatment of RA by Fontana et al.
Macrophages (KG-1) were employed as model cells for the
vesicles’membrane cytoplasmic membrane. The PSi@KG-1
nanoparticulate system did not activate the immune system
in KG-1 macrophages, and covering UnTHCPSi particles
with cell membranes decreased their immunostimulatory activ-
ity [79]. Similarly, nanoparticles coated with macrophage-
derived microvesicles have been shown to target RA. The
monocytes’intrinsic ability to target inflammation motivated
the development of macrophage-derived microvesicle-coated
nanoparticulate systems (MMV-coated nanoparticulate
systems, MNP) for the treatment of RA. The MMV was
generated through the application of a novel strategy. It
was found that the application of cytochalasin B (CB)
Fuse cell membrane
A cell
B cell
Cell membrane
components
Enhance inherent
function Add new function
NPs
NPs
Proteins
External stimuli
Increase inherent components
Carbonhydrates
Add new components
Figure 6: Role of the cell membrane to encapsulate nanoparticulate systems. Reproduced with permission from [78].
10 Journal of Nanomaterials

increased MMV secretion by loosening the macrophages’
cytoskeleton-to-membrane link. The MMV proteome pro-
file was examined using iTRAQ (isobaric tags for relative
and absolute quantitation). This suggests that MMV has
similar bioactivity to RA-targeting macrophages, based on
its membrane proteins. Microparticles were examined both
in vitro and in vivo after being coated with MMV and poly
(lactic-co-glycolic acid) (PLGA) nanoparticulate systems.
In vitro, MNP bound to inflamed HUVECs much more
strongly than the red blood cell membrane-coated nanopar-
ticulate systems (RNP). In a CIA mouse model, MNP
showed a much greater ability to target compared to bare
NP and RNP. In a proteomic investigation, Mac-1 and
CD44 were found to have a significant role in the MNP’s
unique capacity to target. T-RNP-encapsulated Tacrolimus
(a model medicine) greatly slowed the progression of the
disease in mice. As a potential and plentiful source of
macrophage-mimicking material, MMV has been demon-
strated in this study to be an effective biomimetic vehicle
for RA targeting and treatment [80]. A platelet membrane
is also applied to the nanoparticles to treat RA with them.
For the treatment of RA, platelet-mimetic nanoparticulate
systems (PNPs) were produced that mimic the structure of
platelets. Poly(lactic-co-glycolic acid) nanoparticulate sys-
tems (PNPs) were coated with a whole platelet membrane
by platelet receptor-mediated adhesion, resulting in PNPs
having a wide range of functional receptors. The platelet
membrane covering the nanoparticulate systems made
them more stable and better suited for passive targeting.
Using P-selectin and GVPI recognition, the authors were
able to increase PNP binding to inflamed endothelium
in vitro and accumulation in joints of a CIA animal model
of RA. It was demonstrated that PNPs might have targeted
RA tissues similar to natural platelets via several routes. As
an added benefit, PNPs were implanted with the model drug
FK506, which was then administered to patients with RA
[81]. According to a study by Zhang et al., nanoparticulate
systems coated with a neutrophil membrane were found to
be effective in reducing joint damage and inflammation in
patients with RA. Nanoparticulate systems are covered with
neutrophil membranes by fusing the membranes to poly-
meric cores. The antigenic exterior and related membrane
activities of the parent cells were carried over into these
nanoparticulate systems, making them ideal decoys for
biological agents that target neutrophils. Proinflammatory
cytokines were neutralized, synovial inflammation was
reduced, and the nanoparticulate systems penetrated deep
into the cartilage matrix to give significant chondroprotec-
tion against joint damage. Human transgenic mice were
used to study the efficiency of neutrophil membrane-
coated nanoparticulate systems in treating arthritis, which
was shown to lessen joint damage and the severity of arthri-
tis in mice produced by collagen [82].
4.2. Exosomes Encapsulated Nanoparticulate Systems. Exo-
somes are small intracellular membrane-based vesicles of
varying compositions that participate in a variety of biolog-
ical and pathological processes. Exosomes have significant
advantages over other nanoparticulate drug delivery tech-
nologies such as liposomes and polymeric nanoparticulate
systems in that they are nonimmunogenic due to their sim-
ilar composition to the body’s cells [83, 84]. Glucocorticoids
(GCs) have a powerful antirheumatoid effect. However, their
clinical applicability is limited due to nonspecific distribu-
tion after systemic administration, as well as significant
adverse responses after long-term treatment. Exosomes are
newly applied for the treatment of RA and much less
research work is done yet.
Yan et al. reported exosome-derived biomimetic nano-
particulate systems targeted to inflamed joints for improved
RA treatment. Glucocorticoids (GCs) are highly effective in
the treatment of RA (RA). However, clinical applicability is
constrained by their nonspecific distribution following sys-
temic administration and the possibility of major adverse
effects with long-term administration. To improve treatment
and minimize side effects, the authors developed a biomi-
metic exosome (Exo) encapsulating dexamethasone sodium
phosphate (Dex) nanoparticulate systems (Exo/Dex), the
surface of which was modified with a folic acid (FA)-poly-
ethylene glycol- (PEG-) cholesterol (Chol) compound to
achieve an FPC-Exo/Dex active targeting drug delivery
system. By inhibiting pro-inflammatory cytokines and
enhancing anti-inflammatory cytokines, this approach
demonstrated increased endocytosis and an effective anti-
inflammatory impact against RAW264.7 cells in vitro. Fur-
ther, biodistribution studies revealed that FPC-Exo/Dex
fluorescence intensity was greater than that of other Dex for-
mulations in joints, implying that it accumulates more
readily at inflammatory sites. FPC-Exo/Dex preserved the
bone and cartilage of CIA mice better and dramatically
reduced inflammatory joints in an in vivo biodistribution
trial. Following that, in vivo safety evaluations revealed
that this biomimetic drug delivery system exhibited mini-
mal hepatotoxicity and an acceptable level of biocompati-
bility [29].
5. Conclusions and Future Perspective
RA is an autoimmune musculoskeletal condition that has
resulted in significant disability in individuals and has a
global influence on people’s life. Thus, efficient treatment
of RA is critical for relieving patients’discomfort and
increasing the cure rate. Nanotechnology has been applied
for RA treatment. Nanoparticulate systems have signifi-
cantly improved the targeted drug delivery and enhanced
in vitro and in vivo effects of drugs with reduced side effects
has been achieved successfully. Although nanotechnology is
in its infancy, it has the potential to improve disease diagno-
ses, treatment, and research. The commercial and service
industries’performance validates the idea that nanotechnol-
ogy would someday play a substantial role in clinical prac-
tice. Nanotechnology can dramatically lower the cost of
many existing therapies and enable a variety of creative
applications and reduce the negative effects. Nanotechnol-
ogy enables more precise treatment techniques, which may
result in more effective and durable implants, lower infection
rates, and enhanced bone and tendon healing. The theoreti-
cal benefits of nanomedicine are beginning to be realized,
11Journal of Nanomaterials

particularly in the realm of immune disorders as well,
because of massive fundamental scientific research efforts.
However, additional research is necessary to fully under-
stand the safety and usefulness of this innovative technology.
As the advances in medical understanding and technol-
ogy could lead to new treatment options in the future, there
are certain limitations as well. Even though NPS has demon-
strated numerous advantages in drug delivery, some issues
must be addressed before clinical application may proceed.
As the liposomes have been utilized in clinical for drug deliv-
ery, most drug toxicities have been reduced when they are
coated with liposomes; however, it is not the optimal vehicle
for water-soluble medicines. As for metal carrier, many are
not stable, which limit their application, e.g., zinc oxide.
Similarly, CNT is a potential vehicle with outstanding bio-
compatibility, but it must be improved in its capacity to tar-
get specific cells. Therefore, reducing biological toxicity and
maintaining their targeting and bioimaging ability are the
future directions in drug delivery. A better understanding
of anti-inflammatory disorders and focused usage of nano-
particulate systems for diverse diseases would significantly
increase treatment effects and lessen the adverse effects.
Ethical Approval
This study does not involve any animals or humans studies.
Consent
All authors approved the final version of the manuscript.
Conflicts of Interest
All the authors declare that they have no financial or any
other competing interests.
Authors’Contributions
Wenqing Liang, Hengguo Long, and Jiayi Zhao prepared the
draft and wrote the manuscript. Yijun Yu and Zunyong Liu
helped in preparing the figures. Wenyi Ming and Hongming
Lin refined and arranged the contents of the manuscript. All
authors approved the final manuscript. Wenqing Liang and
Yijun Yu contributed equally to this work.
Acknowledgments
This work was supported by the Public Technology Applied
Research Projects of Zhejiang Province (LGF22H060023 to
WQL), the Medical and Health Research Project of Zhejiang
Province (2022KY433 to WQL), the Traditional Chinese
Medicine Science and Technology Projects of Zhejiang
Province (2022ZB382 to WQL and JYZ), and the Research
Fund Projects of The Affiliated Hospital of Zhejiang Chinese
Medicine University (2021FSYYZY45 to WQL).
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