Biomedical Technology 4 (2023) 1–10

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Biomedical Technology
journal homepage: www.keaipublishing.com/en/journals/biomedical-technology

Review

Developing engineering technologies for the treatment of systemic

lupus erythematosus
Xubin Hao a, Yuze Wang a, Rui Liu a, Dagan Zhang a, *, Bin Kong a, b, **, Jun Liang a, ***,
Lingyun Sun a
a
Department of Rheumatology and Immunology, Institute of Translational Medicine, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing,
210008, China
b
Department of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, 518060, China

A R T I C L E I N F O A B S T R A C T

Keywords: Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organs and tissues.
Engineering technology However, only a handful of new drugs have been FDA-approved for SLE since the 1950s. Therefore, novel
Systemic lupus erythematous treatments for SLE are urgently needed to be developed. In recent years, various engineering technologies such as
Nanocarrier
tissue engineering, organs-on-chips, and intelligent delivery systems have been rapidly developed in the field of
Drug delivery
biomedicine. Notably, engineered nanocarriers and cell-based therapies can address the problems faced by
Treatment
traditional drug delivery and cell transplantation. They have proven effective in the treatment of many areas of
disease, including autoimmune diseases. This is an important opportunity to break through the limited treatment
options for SLE. In this review, we summarize the application progresses of engineering technologies and also
propose their challenges in SLE treatment. This paper aims to help readers to understand the perspective of
engineering technologies on the direction of SLE treatments in forthcoming years.

1. Introduction
Systemic lupus erythematosus (SLE), also known as lupus, is a het-
erogeneous autoimmune disease characterized by chronic inflammation
[1]. Patients with lupus lose immune tolerance and produce numerous
autoantibodies that attack their healthy tissues [2]. If not treated in time,
the disease will recur and cause irreversible damage to the affected or-
gans, eventually leading to the death of the patient [3]. Although much of
the pathophysiology of SLE has been uncovered in recent years, sup-
pression of disease activity and reduction of organ damage remain the
mainstay of lupus management by rheumatologists [4]. Medications
commonly used to treat SLE include glucocorticoids, nonsteroidal
anti-inflammatory drugs (NSAIDs), antimalarials, and immunosuppres-
sants [5,6]. However, these drugs have poor specificity, and long-term
use will be accompanied by severe or even life-threatening adverse re-
actions [7]. Encouragingly, the advent of belimumab in 2011 broke the
plight of no new drug available for lupus patients for nearly 60 years [8].
However, belimumab has narrow indications and some adverse reactions
[9,10]. Hence, the development of new treatments for SLE cannot wait
any longer.
In recent years, the development of engineering technology has given
birth to biomedical engineering. Tissue engineering, intelligent delivery
systems, organs-on-chips, etc. shine in many fields [11–13]. Among
them, engineered nanocarriers and cell-based therapies have been
rapidly applied and developed in various diseases, including autoim-
mune diseases [14,15]. Nanocarriers commonly used for disease treat-
ment include synthetic liposomes, polymeric nanoparticles, biologically
derived cell membrane (CM)-coated nanoparticles, and extracellular
vesicles (EVs). Nanocarriers can improve the solubility and accumulation
of traditional drugs in inflamed tissues through enhanced permeability
and retention (EPR) effects [16], or enable active targeting through
surface modification [17]. When combined with CM coating technology,
nanocarriers can achieve long blood circulation and inherit some specific
functions of the source cells [18]. Besides, the development of engi-
neering technology has also led to engineered cell growth. In the treat-
ment of SLE, chimeric antigen receptor-T (CAR-T) cells and engineered

* Corresponding author.
** Corresponding author. Department of Rheumatology and Immunology, Institute of Translational Medicine, The Affiliated Drum Tower Hospital of Nanjing
University Medical School, Nanjing, 210008, China.
*** Corresponding author.
E-mail addresses: zhang_dagan@126.com (D. Zhang), kongbin13@163.com (B. Kong), 13505193169@139.com (J. Liang).

https://doi.org/10.1016/j.bmt.2023.02.002
Received 30 January 2023; Received in revised form 16 February 2023; Accepted 19 February 2023
Available online 22 March 2023
2949-723X/© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
X. Hao et al.
mesenchymal stem cells (MSCs) have been explored [19,20]. Preclinical
and clinical achievements of CAR-T cell therapy in refractory SLE are
encouraging. Engineered MSCs can enhance the stability of MSCs
transplantation therapy and provide other routes for MSCs trans-
plantation to solve the problem of intravenous infusion [21].
In this review, we first introduce the main drugs for the clinical
treatment of SLE and their shortcomings. Subsequently, we elaborate on
the development and achievements of engineering technologies applied
to SLE therapies. The engineering technologies mainly include nano-
carriers and cell-based therapies (Fig. 1). Finally, the prospects of engi-
neering technologies in the field of SLE treatment are discussed.
Therefore, this review is expected to provide comprehensive and helpful
information for researchers exploring better therapies for SLE.
2. Current clinical therapeutic approaches
2.1. Glucocorticoids
Glucocorticoids are still first-line options and have been used to treat
SLE for more than 60 years [22]. The potent and rapid anti-inflammatory
Fig. 1. Schematic illustration of engineering technologies for SLE treatment.
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Biomedical Technology 4 (2023) 1–10
and immunosuppressive properties of glucocorticoids make them useful
in both quiescent and active phases of disease [23]. However, gluco-
corticoids have many notorious adverse events, including affecting
metabolism, bone density, and increasing the risk of infection, especially
for long-term use [7]. Despite widespread acceptance that glucocorti-
coids have a beneficial effect on suppressing inflammation in SLE, several
studies have also shown that long-term glucocorticoid therapy for
maintaining remission is connected with a higher chance of organ
damage [24]. Therefore, whether to discontinue glucocorticoids in pa-
tients with lupus in remission still needs to be explored [25].
2.2. NSAIDs
NSAIDs are commonly used to manage joint pain, fever, serositis, and
headache in patients with SLE [26]. NSAIDs inhibit the cyclooxygenase
(COX) enzymes (COX-1 and COX-2), which are involved in the produc-
tion of prostaglandins [27]. While non-selective NSAIDs exert analgesic
effects, they can also cause adverse gastrointestinal and kidney reactions.
Selective COX-2 inhibitors such as celecoxib are safer for the gastroin-
testinal tract but can increase the risk to the cardiovascular system.
X. Hao et al.
Therefore, the type and dose of NSAIDs must be individualized according
to the patient's gastrointestinal and cardiovascular risk stratification
[28].
2.3. Antimalarials
Antimalarial drugs are the cornerstone of lupus treatment [29]. The
first use of antimalarials in SLE patients probably dates back to 1894,
when J. S. Payne described the successful treatment of a lupus rash with
quinine. During World War II, it was found that quinacrine, used to
prevent malaria, could relieve some of the symptoms of soldiers suffering
from rheumatism, which led to research on antimalarial drugs for
rheumatic disease [30]. Later, in the 1950s, chloroquine and hydroxy-
chloroquine came out one after another and have been used for treating
SLE for more than 60 years. Nowadays, hydroxychloroquine is accepted
globally for SLE patients without contraindications, even in lupus
nephritis patients and pregnant women [31,32]. Of course, retinopathy,
gastrointestinal discomfort, and cutaneous reactions still need attention
[33].
2.4. Immunosuppressants
When lupus is severe or vital organs are involved, immunosuppres-
sive agents are often utilized with glucocorticoids to control the disease
activity. For III and IV lupus nephritis, cyclophosphamide, mycopheno-
late mofetil (MMF), and azathioprine are often used as first-line thera-
peutic drugs [34]. A similar medication tactic is also used in patients with
neuropsychiatric SLE (NPSLE) [35]. New immunosuppressants such as
leflunomide, cyclosporine, and tacrolimus have also been gradually
introduced into the treatment of SLE, providing more alternatives for
treatment [36]. Encouragingly, in January 2021, voclosporin, an oral
calcineurin inhibitor immunosuppressant, was approved by the FDA in
combination with MMF for adults with active lupus nephritis [37,38].
However, immunosuppressants have a wide range of effects and poor
targeting, leading to side effects such as infection and organ damage.
2.5. Biologic agents
In recent years, with a better understanding of the pathogenesis of
SLE, many biologics have been developed to treat lupus. In 2011, the FDA
approved belimumab for the treatment of lupus, which is the first new
drug since hydroxychloroquine's approval for lupus in 1955 [8]. In July
2021, the FDA approved anifrolumab, a human monoclonal antibody to
type I interferon receptor subunit 1, for treating adult patients with
moderate-to-severe SLE [39]. Many other biologics in development for
the treatment of lupus hold great potential. Regarding engineered bio-
logical agents, many excellent articles have been summarized before [6,
40], so they are not discussed in this review.
3. Engineering technologies-based treatment of SLE
3.1. Nanocarriers
Nanocarriers commonly used in lupus treatment research mainly
include polymeric nanoparticles, micelles, liposomes, and nanogels.
3.1.1. Polymeric nanoparticles
Polymeric nanoparticles are widely used for drug delivery due to their
excellent biocompatibility, degradability, and sustained release proper-
ties [41]. Polymeric nanoparticles are the most studied nanomaterials for
lupus therapy compared to other nanocarriers. Immunosuppressants can
be targeted for delivery through polymeric nanoparticles to address their
high non-response rates and adverse effects [42]. Recently, Ganugula
et al. developed oral cyclosporine A (CsA)-loaded nanoparticles for the
lymphatic system targeting to treat lupus. Due to high lipid solubility,
low permeability, and nephrotoxicity, the use of CsA in lupus is limited
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Biomedical Technology 4 (2023) 1–10
[43]. Thus, they fabricated polymeric nanoparticles conjugated to a small
molecule gambogic acid (P2Ns-GA) to increase the solubility and tar-
geting of CsA. Gambogic acid is a ligand targeting CD71, which is
expressed by the intestinal epithelia, Peyer's patches, and lymphocytes.
After incubation with peripheral blood mononuclear cells (PBMCs) in
vitro for 1 h, P2Ns-GA were internalized whereas P2Ns were mostly
constricted to the cell surface (Fig. 2a). In vivo drug distribution experi-
ments showed that the concentration of P2Ns-GA-CsA in lymph nodes
was 18 times higher than that of free CsA group. Eventually, after
P2Ns-GA-CsA treatment, various disease indicators of lupus mice were
significantly improved [44]. Jiang et al. prepared mycophenolic acid
(MPA)-loaded dextran (MPA@Dex-MPA) nanoparticles to improve the
pharmacokinetics of MPA. It was found that MPA@Dex-MPA nano-
particles mainly accumulated in the spleen and kidney and were
phagocytized by macrophages. After treatment, macrophages were
significantly reduced, predominantly exhibiting an M2-like phenotype. T
cell proliferation was also inhibited in the spleen and kidney (Fig. 2b). All
the results indicated that the MPA@Dex-MPA nanoparticles relieved the
disease progression in MRL/lpr mice [45]. Azathioprine is commonly
used to treat severe SLE but has low solubility and a short half-life. Hu
et al. developed polyhydroxyalkanoate (PHA) nanoparticles encapsu-
lating azathioprine (AZA-PHA) for SLE therapy. AZA-PHA nanoparticles
exhibited slower clearance and more accumulation in the spleen. As a
result, AZA-PHA nanoparticles reduced urinary protein with less toxicity
[46]. Besides immunosuppressants, nanocarriers have also been devel-
oped to deliver RNAs or some cytokines for the treatment of lupus [47].
MicroRNAs (miRNAs) are endogenous noncoding RNAs that regulate
mRNA stability and translation. Collecting reports disclosed that miRNA
dysfunction is associated with the immune disorder in SLE. For example,
miRNA-125a is able to stabilize regulatory T cell-mediated self-tolerance.
However, it was found to be down-regulated in peripheral T cells of
people with SLE [48]. Zhang et al. constructed polymeric nanoparticles to
protect miRNA-125a from degradation and deliver it to splenic T cells
(Fig. 2c). The results showed that miRNA-125a encapsulated nano-
particles could alleviate lupus by improving the disorder between
effector and regulatory T cells [49].
3.1.2. Micelles
Micelles are small sub-50nm entities self-assembled from water-
soluble amphiphilic surfactants and are frequently served for drug de-
livery [50]. Long-term use of glucocorticoids in lupus patients may lead
to osteoporosis and infection. Jia et al. fabricated a poly(ethylene glycol)
(PEG)-based dexamethasone prodrug (ZSJ-0228) to address this chal-
lenge. The pronounced amphiphilicity of the ZSJ-0228 enables it to
spontaneously self-assemble into micelles in aqueous media, thereby
increasing the water solubility of dexamethasone. As nanocarriers have a
natural tendency to accumulate in inflamed tissues through vascular
leakage [51], the prodrug micelles were found to accumulate in the
inflamed kidney (Fig. 2d). Unlike the results of daily dexamethasone
treatment, monthly ZSJ-0228 treatment greatly relieved lupus nephritis
without significant glucocorticoid-related side effects [52]. Next, the
authors went on to investigate the optimal dose-response relationship of
ZSJ-0228 in lupus nephritis. ZSJ-0228 was injected monthly at a dosage
ranging from 0.5 to 8.0 mg/kg/day dexamethasone equivalent. Urine
protein and other results showed that the most effective dose range for
ZSJ-0228 in NZB/W F1 mice is between 1.0 and 3.0 mg/kg/day dexa-
methasone equivalent (Fig. 2e) [53]. Due to fewer side effects and less
frequent dosing, ZSJ-0228 may become an alternative to glucocorticoids
in patients with SLE.
3.1.3. Liposomes
Liposomes are nanovesicles self-assembled from phospholipids. The
amphipathic properties of liposomes make them ideal carriers for both
hydrophilic and lipophilic drugs, as well as some therapeutic nucleic
acids [54]. The US FDA first approved liposomal doxorubicin in 1995 for
the clinical treatment of cancer [55]. Like polymeric nanoparticles,
X. Hao et al. Biomedical Technology 4 (2023) 1–10

Fig. 2. (a) P2Ns-GA targeted to the lymphatic system. (i). Chemical structure of the P2s-GA polymer. (ii) Confocal imaging of mouse PBMCs incubated with fluo-
rescent (green) P2Ns-GA or P2Ns for 60 min. CD71 (purple), CD3þ T cells (red), and CD20þ B cells (red). Reproduced with permission from Ref. [44] Copyright 2020
The Authors. (b) MPA@Dex-MPA nanoparticles targeted to the spleen and kidney. The scheme of the (i) fabrication and (ii) application of MPA@Dex-MPA nano-
particles. Reproduced with permission from Ref. [45] Copyright 2022 The Authors. (c) Schematic illustration of the microRNA-125a-loaded polymeric nanoparticles
restoring effector/regulatory T Cells balance. Reproduced with permission from Ref. [49] Copyright 2020 American Chemical Society. (d) Micelle-forming dexa-
methasone prodrug reduced glucocorticoid side effects. (i) Structure of PEG-based amphiphilic dexamethasone prodrug ZSJ-0228. (ii) ZSJ-0228 was mainly
distributed in the inflamed kidney Reproduced with permission from Ref. [52] Copyright 2018 American Chemical Society. (e) A dose-escalation design to establish
the optimal dose-response relationships for ZSJ-0228 in treating lupus nephritis. Reproduced with permission from Ref. [53] Copyright 2021 American Chemi-
cal Society.

liposomes have many applications in lupus treatment research. As
glomerular mesangial cells are vital cells involved in lupus nephritis,
Scindia et al. developed novel immunoliposomes for renal glomerulus
targeting. They noticed that α8 integrin was expressed in the glomeruli of
normal and nephritic mice. Thus, they built liposomes conjugated with
anti-α8 integrin for mesangial-targeted delivery. Anti-α8 integrin lipo-
somes discovered in glomeruli and mesangial cells revealed that this
novel liposomal delivery system provides a targeted strategy for lupus
nephritis therapy [56]. Moallem et al. constructed a liposomal steroid
formulation for inflamed tissues targeting through EPR effects to treat
MRL/lpr mice [57]. Trans-activating transcriptional activator (TAT)
peptides are frequently utilized for facilitating cellular uptake [58]. Diao
et al. fabricated TAT peptide-cationic liposomes to co-delivery dihy-
droartemisinin (DHA) and high-mobility group box 1 (HMGB1) siRNA
(TAT-CLs-DHA/siRNA) for SLE treatment (Fig. 3a). Hyperactivation of
the Toll-like receptor-4 (TLR4) signal pathway is closely associated with
lupus nephritis [59]. TLR4 is the primary receptor in the inflammatory
cascade of HMGB1. The results revealed that TAT-CLs-DHA/siRNA
significantly reduced the expression of TLR4 and effectively alleviated
lupus nephritis [60]. Phagocytes in lupus patients have inefficient
removal of apoptotic cells, leading to the assemblage of self-antigens,
which eventually induce autoantibodies to attack healthy tissues. Xu
et al. designed a phosphatidylserine (PS) conjugated liposome-coated
gold nanocage (AuNC) encapsulating T0901317 (PS-lipo-
s-AuNC@T0901317) to treat SLE (Fig. 3b). T0901317 is a liver X
receptors (LXRs) agonist regulating both the phagocytic activity and in-
flammatory response in macrophages. The authors found that
PS-lipos-AuNC@T0901317 enhanced the removal of apoptotic cells,
leading to reduced production of anti-dsDNA autoantibodies and in-
flammatory response [61]. These results provide another idea to improve
the clearance of self-antigens by apoptotic cells to treat lupus, which is
different from the delivery of glucocorticoids or immunosuppressants by
most nanocarriers. Exaggerated cooperation of autoreactive B cells and
CD4þ T helper (Th) leading to autoantibody production is a challenge for
lupus treatment [62]. Targeting the SLE-specific upregulation of cos-
timulatory molecules ICOS or CD40L on Th can block Th-B activation,
but the current blockade of a single costimulatory molecule is ineffective.
Zhang et al. fabricated rapamycin-encapsulated costimulatory
ICOS/CD40L-bispecific liposomal nanoparticles to specifically target SLE
Th cells (Fig. 3c). The results exhibited that these bispecific nanoparticles
effectively inhibited Th–B cell activation and attenuated SLE progression
[63].
3.1.4. Nanogels
Nanogels are nanosized crosslinked hydrophilic polymeric networks
that are ideal carriers for drug and nucleic acid delivery [64]. The
application of nanogels in the treatment of SLE was mainly studied by
Fahmy and colleagues, who mainly explored the delivery of the immu-
nosuppressant MPA to dendritic cells (DCs) by nanogels to alleviate lupus
nephritis (Fig. 3d). First, they found that the MPA-loaded nanogels

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X. Hao et al. Biomedical Technology 4 (2023) 1–10

Fig. 3. (a) Structure and treatment strategy of TAT-CLs-DHA/siRNA. Reproduced with permission from Ref. [60] Copyright 2019 The Authors. (b) Schematic
illustration of the preparation procedure of PS-lipos-AuNC@T0901317. Reproduced with permission from Ref. [61] Copyright 2019 Elsevier Ltd. (c) Schematic
representation of ICOS/CD40L bispecific RAP nanoparticles for SLE treatment. Reproduced with permission from Ref. [63] Copyright 2022 Elsevier Ltd. (d) Schematic
illustration of the MPA-loaded nanogels. Reproduced with permission from Ref. [65] Copyright 2013 The American Society for Clinical Investigation.

prolonged survival and attenuated lupus nephritis in NZB/W F1 mice
compared with free MPA [65]. They then revealed that the nanogels
efficiently internalized by DCs and inhibited the maturation of DCs
characterized by the downregulation of costimulatory molecules and
reduction of inflammatory factors. DCs are important in regulating im-
munity and tolerance and play an important role in the pathogenesis of
lupus [66]. The authors also constructed CD4-targeted MPA-loaded
nanogels to explore whether they could inhibit the proliferation of T
cells. The results showed a decrease in the number of CD4þ T cells in
lupus mice, but the overall efficacy was similar to that of non-targeted
nanogels [65]. Efficacious internalization is an important factor for the
function of nanogels, so the authors next went on to investigate whether
other classes of nanomaterials can also be effective. They compared the
most commonly used nanocarrier poly (lactic-co-glycolic acid) (PLGA)
nanoparticles. They found that nanogels were more efficiently internal-
ized by dendritic cells and inhibited dendritic cell maturation in vitro.
These results displayed that the ease of internalization of nanogels is an
important factor for their therapeutic efficacy compared with other
nanomaterials [67].
3.2. Cell-based therapies
The application of cell-based therapies or carriers for SLE treatment
generally includes four aspects: CAR-T cell therapy, engineered MSCs,
CM-coated nanoparticles, and engineered EVs.
3.2.1. CAR-T
CAR-T cells are T cells engineered to express a CAR consisting of an
extracellular antigen-recognizing domain and an intracellular T cell-
activation domain [68]. When T cells are armed with CAR, they can
kill target cells by recognizing specific antigens. CAR-T cell therapy was
first approved by the FDA in 2017 for its efficacy against CD19þ tumors
[69]. CD19 is expressed in almost all stages of B cells [70], the most
important cells in the pathogenesis of SLE. Therefore, a series of break-
throughs of CD19-targeted CAR-T cells in lymphoma has attracted re-
searchers to introduce CAR-T into SLE. CAR-T cell therapy for SLE was
first studied by Kansal and colleagues in two different mouse models of
lupus in 2019. They constructed CD19-targeted CAR-T cells based on
purified CD8þ T cells and demonstrated effective and long-lasting
depletion of B cells following CAR-T cell therapy [71]. In parallel, Jin
et al. prepared CD19-targeted CAR-T cells based on total T cells to treat
lupus in MRL/lpr mice (Fig. 4a). They found that infusion of CAR-T cell
therapy can effectively eliminate B cells and prolong survival both before
and after the onset of the disease [70]. The experiments of the above two
different teams were all carried out on lupus mice, which provided a basis
for CAR-T application in lupus patients. Coincidentally, in August 2021,
another two teams successively reported the successful application of
CAR-T therapy in the treatment of lupus patients. First, Mougiakakos
et al. reported that they developed CD19-targeted CAR-T cells to treat a
20-year-old woman with refractory SLE with type IIIA nephritis (Fig. 4b).
The woman did not respond obviously to conventional medical therapy
as well as novel biologics including belimumab and rituximab. After
suspending all treatment except low-dose glucocorticoids, the woman
was treated with CAR-T cells [72]. Encouragingly, the results showed
that the SLE Disease Activity Index (SLEDAI) of this woman returned to
0 [19]. Similarly, Zhang et al. reported that a case of SLE with diffuse
large B-cell lymphoma was successfully treated with CD19-BCMA com-
pound CAR-T cell therapy [73]. Both reports above were based on indi-
vidual case studies but still revealed that CAR-T cell therapy holds huge
promise in SLE therapy. Recently, CAR-T cell therapy was used in 5

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Fig. 4. (a) Working scheme of CAR-T cell manufacture and adoptive transfer in a mouse experiment. Reproduced with permission from Ref. [70] Copyright 2020 CSI
and USTC. (b) Workflow of anti-CD19 CAR-T cell treatment for the SLE patient. Reproduced with permission from Ref. [19] Copyright 2021 The Authors. (c)
Schematic demonstrating the fabrication of adhesive porous particles with MSCs encapsulation for immunomodulation after intraperitoneal transplantation in MRL/lpr
mice. Reproduced with permission from Ref. [21] Copyright 2020 The Authors. (d) Fabrication of the microgels with human MSCs encapsulation via microfluidic
electrospray for immunoregulation after subcutaneous transplantation into MRL/lpr mice. Reproduced with permission from Ref. [20] Copyright 2022 Elsevier Ltd.

young SLE patients with multiorgan involvement. As in other studies,
glucocorticoids, immunosuppressants, and biologics were ineffective in
these 5 patients. Three months after a single infusion of CAR-T cells, the
average SLEDAI of all patients was 0. Furthermore, drug-free remission
was maintained during a median follow-up of 8 months [74]. Unlike
individual case studies, the results of these 5 patients make the applica-
tion of CAR-T in lupus promising to be a study with a larger sample.
3.2.2. Engineered MSCs
MSCs are fibroblast-like pluripotent stem cells without hematopoietic
function [75]. They can modulate innate and adaptive immunity for
immunomodulatory functions. Therefore, MSC transplantation has been
introduced to treat SLE. Both preclinical and clinical studies have
revealed that allogeneic MSC transplantation could effectively relieve the
clinical symptoms of patients with refractory lupus [76,77]. However,
some studies have shown that MSC transplantation is ineffective, which
may be related to the immune regulation elasticity of MSCs and the
susceptibility to the microenvironment [78]. Hence, engineered MSCs
such as genetic modification can compensate for and increase the func-
tion of MSCs. Che et al. found that lupus bone marrow MSCs exhibit
functional deficits in normal B-cell suppression compared with normal
bone marrow MSCs. They further explored that knocking down CCL2 in
normal MSCs disrupted their ability to suppress B cells. Thus, they con-
structed engineered lupus MSCs overexpressing CCL2, which effectively
restored the ability of MSCs to regulate B cells and alleviated lupus
nephritis [79]. Likewise, genetically modified MSCs overexpressing IL-37
enhanced immunosuppression and reduced systemic inflammation in
lupus mice [80]. Another factor affecting the clinical efficacy of MSCs
therapy is that after intravenous infusion, MSCs are easily lysed by im-
mune cells and maintain a short time in vivo [81,82]. To overcome this
problem, Zhao and colleagues recently synthesized microparticles and
microgels to encapsulate MSCs by microfluidic electrospray technology
for treating lupus mice [20,21]. First, inspired by the natural micro-
structure of the sand tower worm nest, they fabricated MSCs encapsu-
lated adhesive porous particles (Fig. 4c). After intraperitoneal injection,
compared with unencapsulated MSCs, microsphere encapsulation can
prolong the existence time of MSCs in vivo, which is of great significance
for exerting the therapeutic effect of MSCs. Meanwhile, MSCs encapsu-
lated microparticles induced macrophages to shift to the M2 phenotype
and powerfully relieved lupus nephritis [21]. Similarly, subcutaneous
injection of microgels encapsulated with MSCs also had a good effect on
MRL/lpr mice (Fig. 4d) [20]. These results provide some new delivery
approaches for MSCs transplantation beyond just intravenous infusion.
3.2.3. CM-coated nanoparticles
Although nanocarriers have achieved a series of achievements in pre-
clinical and clinical studies, there are still some areas for improvement. To
avoid immune clearance, the surface of nanocarriers usually needs to be
modified with PEG to improve blood circulation time. However, PEGyla-
tion will induce the body to produce antibodies, which will accelerate the
body's clearance of nanocarriers after multiple injections [83]. In addition,
it is often necessary to incorporate some ligands to increase the targeting

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of nanocarriers, but the characterization and preparation of ligands are
complicated. To improve these deficiencies, in 2011, Zhang and col-
leagues proposed for the first time to camouflage nanocarriers by coating
PLGA nanoparticles with red blood cell (RBC) membrane [84]. The blood
circulation experiments showed that the elimination half-life of
RBC-coated nanoparticles was 39.6 h, which was longer than that of
PEGylated nanoparticles (15.8 h). Since then, CM coating technology
derived from different types of cells has been rapidly applied in cancer and
other fields. However, the application of cell membrane coating technol-
ogy in SLE is only in the early exploration stage. For the first time, our
group applied RBC membrane-camouflaged nanoparticles to treat lupus
mice [85]. Due to the large variability in blood concentrations of CsA, we
constructed RBC-coated and CsA-loaded PLGA nanoparticles (CsA-RNPs)
to optimize the pharmacokinetic properties of CsA (Fig. 5a). According to
the whole blood drug concentration curve, the half-life of CsA-RNPs is
2.05 times longer than that of uncoated nanoparticles. After CsA-RNPs
treatment, the lupus serological indicators and organ damage have been
effectively improved [85]. Guo et al. pioneered the use of cancer cell
membrane-coated nanoparticles named IM-MNPs to treat lupus mice
(Fig. 5b). The 4T1 cancer cell was engineered with major histocompati-
bility complex class I (MHC I) deficient to lower immunogenicity. After
incubation with INF-γ, the expression of CD155 and PD-L1 was upregu-
lated in 4T1 cells, which could increase the targeting of nanoparticles to
CD4 T cells. The results revealed that dexamethasone-loaded IM-MNPs
shaped the effector T cell/Treg balance and attenuated the progression of
SLE [86].
3.2.4. Engineered EVs
EVs are lipid bilayer vesicles secreted by various cells for cellular
communication in vivo. Unlike simple liposomes, EVs contain complex
lipids, nucleic acids, and proteins [87]. The most generally studied EVs
are exosomes, 40–100 nm in diameter. Exosomes themselves can regu-
late almost all immune cells (Fig. 5c). At the same time, the vesicle
structure allows them to be used as nanocarriers to deliver nucleic acids
or drugs [88]. Exosomes have been proven to play a critical role in the
pathogenesis of SLE [89]. Several experiments have revealed that exo-
somes can also serve as nanocarriers and biomarkers of SLE [88]. Sun
et al. used exosomes as a transport vehicle to deliver curcumin to target
the inflammatory cells [90]. This approach holds promise for use in SLE.
The properties of exosomes alone are not enough to ensure the enrich-
ment of therapeutic agents in disease tissues, so exosomes are usually
engineered to improve targeting ability [91]. Fang et al. constructed
engineered NIH 3T3 cell membrane nanovesicles expressing CD40 (CD40
NVs) to target CD40/CD40L axis to block B cell signal activation
(Fig. 5d). It was found that MMF-loaded CD40 NVs inhibited B cell
activation and alleviated the disease progression in MRL/lpr mice [92].
One problem with MSCs transplantation is the difficulty of cell storage
and possible tumor induction. Fortunately, some studies have shown that
exosomes from MSCs have similar immunomodulatory functions as
MSCs. Therefore, exosomes with high stability and easy long-term stor-
age are promising as cell-free therapy for SLE [78]. Due to the excellent
properties of EVs, lupus-related researchers should pay more attention to
applying EVs and engineered EVs to SLE treatment.

Fig. 5. (a) Diagrammatic overview of the fabrication and application of CsA-RNPs. Reproduced with permission from Ref. [85], Copyright 2022 The Authors. (b)
Schematic of the preparation process and application of dexamethasone-loaded IM-MNPs. Reproduced with permission from Ref. [86] Copyright 2022 Elsevier Ltd. (c)
Immunoregulatory functions of EVs. Reproduced with permission from Ref. [93] Copyright 2022 Springer Nature Limited. (d) Schematic overview of MMF-loaded
CD40 NVs for SLE treatment. Reproduced with permission from Ref. [92] Copyright 2023 Wiley-VCH GmbH.

7
X. Hao et al.
4. Conclusion and perspectives
SLE is a complicated autoimmune disease in which nearly all crucial
elements of the immune system are involved in the underlying patho-
genic mechanism. From the antimalarial drugs approved for lupus in the
1950s to the present, we have a more complete and in-depth under-
standing of lupus pathogenesis and management. However, it was not
until 2011 that belimumab was approved by the FDA for the treatment of
lupus, filling the dilemma of no new drug available for nearly 60 years.
Rapid advances in engineering technology bring new opportunities for
lupus treatment. Compared with traditional therapeutic methods, nano-
carriers have multiple advantages in agents delivery for the treatment of
SLE, such as enhanced drug solubility, sustained release, and passive
accumulation at inflammatory sites. When the surface of nanocarriers is
engineered, active targeting of tissues or cells in need of delivery can also
be achieved. Nanocarriers currently in lupus research are mainly used for
the selective delivery of glucocorticoids and immunosuppressants. The
work of Xu et al. provides another idea to improve the clearance of self-
antigens by apoptotic cells for treating lupus with nanocarriers [61].
Despite the excellent performance, it cannot be ignored that the
biocompatibility and efficacy of nanocarriers in the human body still
need to be further explored. CAR-T cell therapy has shown encouraging
achievements in both preclinical and clinical studies in refractory SLE.
The effect of CAT-T cell therapy lasted for a long time, and the patient's
SLEDAI almost returned to 0. However, the largest sample in the study of
CAR-T treatment of lupus is only 5 patients, and further research is
needed on larger samples and whether it can treat early or mild SLE.
Engineered MSCs are expected to solve the problem that cell trans-
plantation in some patients is ineffective partially because of the strong
immunomodulatory plasticity of MSCs. Microparticles and microgels
encapsulating MSCs also provide intraperitoneal and subcutaneous
routes for MSCs transplantation. However, these studies on engineered
MSCs are still at the stage of animal models. CM-coated nanoparticles and
EVs are currently considered as next-generation drug delivery platforms.
The efficacy of nanoparticles encapsulated in RBC membrane and tumor
CM has been effectively tested in MRL/lpr mice, but other CM could also
be introduced to treat lupus. For example, neutrophil membrane-coated
nanoparticles can target sites of inflammation, which has been shown to
work well in mice with rheumatoid arthritis. EVs themselves can be used
as therapeutic agents or as vehicles for the delivery of drugs or nucleic
acids. Therefore, more research on engineered EVs should focus on
treating SLE. In general, engineering technology is a significant oppor-
tunity to break the dilemma of no new drugs available for SLE.
CRediT authorship contribution statement
Xubin Hao: Conceptualization, Writing – original draft. Yuze Wang:
Writing – review & editing. Rui Liu: Writing – review & editing. Dagan
Zhang: Funding acquisition, Writing – review & editing. Bin Kong:
Funding acquisition, Writing – review & editing. Jun Liang: Conceptu-
alization, Funding acquisition, Writing – review & editing. Lingyun Sun:
Supervision.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgments
This work was supported by the fundings for Clinical Trials from the
Affiliated Drum Tower Hospital, Medical School of Nanjing University
(2022-LCYJ-MS-38), the Puai Medical Research Fund of Beijing Bethune
Charitable Foundation (PAYJ-008), the National Natural Science
8
Biomedical Technology 4 (2023) 1–10
Foundation of China (82102511), the Natural Science Foundation of
Jiangsu (BK20210021), the Research Project of Jiangsu Province Health
Committee (M2021031), the National Natural Science Foundation of
China (82101184), Shenzhen Fundamental Research Program
(JCYJ20210324102809024), Shenzhen PhD Start-up Program
(RCBS20210609103713045).
References
[1] A. Psarras, M. Wittmann, E.M. Vital, Emerging concepts of type I interferons in SLE
pathogenesis and therapy, Nat. Rev. Rheumatol. 18 (2022) 575–590.
[2] R.A. Furie, R.F. van Vollenhoven, K. Kalunian, S. Navarra, J. Romero-Diaz,
V.P. Werth, X. Huang, G. Clark, H. Carroll, A. Meyers, et al., Trial of anti-BDCA2
antibody litifilimab for systemic lupus erythematosus, N. Engl. J. Med. 387 (2022)
894–904.
[3] J. Tian, D. Zhang, X. Yao, Y. Huang, Q. Lu, Global epidemiology of systemic lupus
erythematosus: a comprehensive systematic analysis and modelling study, Ann.
Rheum. Dis. 82 (3) (2023 Mar) 351–356.
[4] M.R.W. Barber, C. Drenkard, T. Falasinnu, A. Hoi, A. Mak, N.Y. Kow,
E. Svenungsson, J. Peterson, A.E. Clarke, R. Ramsey-Goldman, Global epidemiology
of systemic lupus erythematosus, Nat. Rev. Rheumatol. 17 (2021) 515–532.
[5] Systemic lupus erythematosus, Ann. Intern. Med. 172 (2020) ITC81–ITC96.
[6] F. Basta, F. Fasola, K. Triantafyllias, A. Schwarting, Systemic lupus erythematosus
(SLE) therapy: the old and the new, Rheumatology and Therapy 7 (2020) 433–446.
[7] A. Prete, I. Bancos, Glucocorticoid induced adrenal insufficiency, BMJ 374 (2021)
n1380.
[8] C.B. Burness, P.L. McCormack, Belimumab, Drugs 71 (2011) 2435–2444.
[9] X. Yu, N. Chen, J. Xue, C.C. Mok, S.-C. Bae, X. Peng, W. Chen, H. Ren, X. Li,
K. Noppakun, et al., Efficacy and safety of belimumab in patients with lupus
nephritis: subgroup analyses of a phase 3 randomized trial in the east asian
population, Am J Kidney Dis. (2022 Sep 2). S0272-6386(22)00860-5.
[10] H.I. Brunner, C. Abud-Mendoza, D.O. Viola, I. Calvo Penades, D. Levy, J. Anton,
J.E. Calderon, V.G. Chasnyk, M.A. Ferrandiz, V. Keltsev, et al., Safety and efficacy of
intravenous belimumab in children with systemic lupus erythematosus: results from
a randomised, placebo-controlled trial, Ann. Rheum. Dis. 79 (2020) 1340–1348.
[11] N. Sch€afer, S. Gr€assel, New refinements aim to optimize articular cartilage tissue
engineering, Nat. Rev. Rheumatol. 19 (2023) 66–67.
[12] Y. Zhu, L. Cai, H. Chen, Y. Zhao, Developing organs-on-chips for biomedicine, Sci.
Bull. 67 (2022) 1108–1111.
[13] L. Shang, Y. Zhao, W. Cui, Regenerative medicine entering a new era, Small 18
(2022), 2204625.
[14] M. Zheng, H. Jia, H. Wang, L. Liu, Z. He, Z. Zhang, W. Yang, L. Gao, X. Gao, F. Gao,
Application of nanomaterials in the treatment of rheumatoid arthritis, RSC Adv. 11
(2021) 7129–7137.
[15] R. He, L. Li, T. Zhang, X. Ding, Y. Xing, S. Zhu, Z. Gu, H. Hu, Recent advances of
nanotechnology application in autoimmune diseases – a bibliometric analysis, Nano
Today 48 (2023), 101694.
[16] B. Ozbakir, B.J. Crielaard, J.M. Metselaar, G. Storm, T. Lammers, Liposomal
corticosteroids for the treatment of inflammatory disorders and cancer, J. Contr.
Release 190 (2014) 624–636.
[17] D. Peer, J.M. Karp, S. Hong, O.C. Farokhzad, R. Margalit, R. Langer, Nanocarriers as
an emerging platform for cancer therapy, Nat. Nanotechnol. 2 (2007) 751–760.
[18] R.H. Fang, W. Gao, L. Zhang, Targeting drugs to tumours using cell membrane-
coated nanoparticles, Nat. Rev. Clin. Oncol. 20 (2023) 33–48.
[19] X. Jin, Y. Han, J.Q. Wang, L. Lu, CAR-T cell therapy: new hope for systemic lupus
erythematosus patients, Cell. Mol. Immunol. 18 (2021) 2581–2582.
[20] H. Zhu, B. Kong, M. Nie, C. Zhao, R. Liu, Y. Xie, Y. Zhao, L. Sun, ECM-inspired
peptide dendrimer microgels with human MSCs encapsulation for systemic lupus
erythematosus treatment, Nano Today 43 (2022).
[21] M. Nie, G. Chen, C. Zhao, J. Gan, M. Alip, Y. Zhao, L. Sun, Bio-inspired adhesive
porous particles with human MSCs encapsulation for systemic lupus erythematosus
treatment, Bioact. Mater. 6 (2021) 84–90.
[22] A. Fanouriakis, N. Tziolos, G. Bertsias, D.T. Boumpas, Update οn the diagnosis and
management of systemic lupus erythematosus, Ann. Rheum. Dis. 80 (2021) 14–25.
[23] R.S. Hardy, K. Raza, M.S. Cooper, Therapeutic glucocorticoids: mechanisms of
actions in rheumatic diseases, Nat. Rev. Rheumatol. 16 (2020) 133–144.
[24] D. Apostolopoulos, E.F. Morand, It hasn't gone away: the problem of glucocorticoid
use in lupus remains, Rheumatology 56 (2017) i114–i122.
[25] N. Acharya, Glucocorticoid withdrawal in lupus - to do or not to do? Ann. Rheum.
Dis. 81 (2022) e44.
[26] W. Xiong, R.G. Lahita, Pragmatic approaches to therapy for systemic lupus
erythematosus, Nat. Rev. Rheumatol. 10 (2014) 97–107.
[27] A.M. Schjerning, P. McGettigan, G. Gislason, Cardiovascular effects and safety of
(non-aspirin) NSAIDs, Nat. Rev. Cardiol. 17 (2020) 574–584.
[28] M.J. Domper Arnal, G. Hijos-Mallada, A. Lanas, Gastrointestinal and cardiovascular
adverse events associated with NSAIDs, Expet Opin. Drug Saf. 21 (2022) 373–384.
[29] O. Araújo, J. Hernandez-Rodríguez, L. Pelegrín, M. Feliu, M. Boland, H. Hernandez-
Negrín, A. Adan, G. Espinosa, R. Cervera, Why lupus patients discontinue
antimalarials in real life: a 50 years-experience from a reference centre, Lupus 31
(2022) 1344–1354.
[30] S.J. Lee, E. Silverman, J.M. Bargman, The role of antimalarial agents in the
treatment of SLE and lupus nephritis, Nat. Rev. Nephrol. 7 (2011) 718–729.
X. Hao et al.
[31] G. Ruiz-Irastorza, D. Martin-Iglesias, A. Soto-Peleteiro, Update on antimalarials and
systemic lupus erythematosus, Curr. Opin. Rheumatol. 32 (2020) 572–582.
[32] G. Figueroa-Parra, C.M. Gamboa-Alonso, A.L. De-Leon-Ibarra, D.A. Galarza-
Delgado, Update of the EULAR recommendations for the management of SLE: don't
forget chloroquine, Ann. Rheum. Dis. 79 (2019) e114, 2020.
[33] D.J. Wallace, V.S. Gudsoorkar, M.H. Weisman, S.R. Venuturupalli, New insights into
mechanisms of therapeutic effects of antimalarial agents in SLE, Nat. Rev.
Rheumatol. 8 (2012) 522–533.
[34] D.H. Wang, D.J. Wallace, New insights into systemic lupus erythematosus therapies:
2010-2020, J. Clin. Rheumatol. 28 (2022) e217–e221.
[35] N. Schwartz, A.D. Stock, C. Putterman, Neuropsychiatric lupus: new mechanistic
insights and future treatment directions, Nat. Rev. Rheumatol. 15 (2019) 137–152.
[36] A. Mohamed, Y. Chen, H. Wu, J. Liao, B. Cheng, Q. Lu, Therapeutic advances in the
treatment of SLE, Int. Immunopharm. 72 (2019) 218–223.
[37] Y.A. Heo, Voclosporin: first approval, Drugs 81 (2021) 605–610.
[38] M. Kostopoulou, A. Fanouriakis, G. Bertsias, D.T. Boumpas, Treatment of lupus:
more options after a long wait, Ann. Rheum. Dis. 81 (2022) 753–756.
[39] E.D. Deeks, Anifrolumab: first approval, Drugs 81 (2021) 1795–1802.
[40] A. Mohamed, Y. Chen, H. Wu, J. Liao, B. Cheng, Q. Lu, Therapeutic advances in the
treatment of SLE, Int. Immunopharm. 72 (2019) 218–223.
[41] Y. Shao, Z. Yang, Progress in polymer single-chain based hybrid nanoparticles,
Prog. Polym. Sci. 133 (2022), 101593.
[42] D. Rostamzadeh, S.R. Razavi, S. Esmaeili, S. Dolati, M. Ahmahi, S. Sadreddini,
F. Jadidi-Niaragh, M. Yousefi, Application of nanoparticle technology in the
treatment of Systemic lupus erythematous, Biomed. Pharmacother. 83 (2016)
1154–1163.
[43] C.B. Chighizola, V.H. Ong, P.L. Meroni, The use of cyclosporine A in rheumatology:
a 2016 comprehensive review, Clin. Rev. Allergy Immunol. 52 (2017) 401–423.
[44] R. Ganugula, M. Arora, D. Zou, S.K. Agarwal, C. Mohan, M.N.V.R. Kumar, A highly
potent lymphatic system-targeting nanoparticle cyclosporine prevents
glomerulonephritis in mouse model of lupus, Sci. Adv. 6 (2020), eabb3900.
[45] B. Jiang, Y. Zhang, Y. Li, Y. Chen, S. Sha, L. Zhao, D. Li, J. Wen, J. Lan, Y. Lou, et al.,
A tissue-tended mycophenolate-modified nanoparticle alleviates systemic lupus
erythematosus in MRL/lpr mouse model mainly by promoting local M2-like
macrophagocytes polarization, Int. J. Nanomed. 17 (2022) 3251–3267.
[46] J. Hu, M. Wang, X. Xiao, B. Zhang, Q. Xie, X. Xu, S. Li, Z. Zheng, D. Wei, X. Zhang,
A novel long-acting azathioprine polyhydroxyalkanoate nanoparticle enhances
treatment efficacy for systemic lupus erythematosus with reduced side effects,
Nanoscale 12 (2020) 10799–10808.
[47] H. Shimizu, Y. Hori, S. Kaname, K. Yamada, N. Nishiyama, S. Matsumoto, K. Miyata,
M. Oba, A. Yamada, K. Kataoka, T. Fujita, siRNA-based therapy ameliorates
glomerulonephritis, J. Am. Soc. Nephrol. 21 (2010) 622–633.
[48] W. Pan, S. Zhu, D. Dai, Z. Liu, D. Li, B. Li, N. Gagliani, Y. Zheng, Y. Tang,
M.T. Weirauch, et al., MiR-125a targets effector programs to stabilize Treg-
mediated immune homeostasis, Nat. Commun. 6 (2015) 7096.
[49] J. Zhang, C. Chen, H. Fu, J. Yu, Y. Sun, H. Huang, Y. Tang, N. Shen, Y. Duan,
MicroRNA-125a-Loaded polymeric nanoparticles alleviate systemic lupus
erythematosus by restoring effector/regulatory T cells balance, ACS Nano 14 (2020)
4414–4429.
[50] Y. Lu, Z. Yue, J. Xie, W. Wang, H. Zhu, E. Zhang, Z. Cao, Micelles with ultralow
critical micelle concentration as carriers for drug delivery, Nat Biomed Eng 2 (2018)
318–325.
[51] X. Clemente-Casares, P. Santamaria, Nanomedicine in autoimmunity, Immunol.
Lett. 158 (2014) 167–174.
[52] Z. Jia, X. Wang, X. Wei, G. Zhao, K.W. Foster, F. Qiu, Y. Gao, F. Yuan, F. Yu,
G.M. Thiele, et al., Micelle-forming dexamethasone prodrug attenuates nephritis in
lupus-prone mice without apparent glucocorticoid side effects, ACS Nano 12 (2018)
7663–7681.
[53] Z. Zhao, X. Xu, H. Jiang, K.W. Foster, Z. Jia, X. Wei, N. Chen, S.R. Goldring,
M.K. Crow, D. Wang, Preclinical dose-escalation study of ZSJ-0228, a polymeric
dexamethasone prodrug, in the treatment of murine lupus nephritis, Mol. Pharm. 18
(2021) 4188–4197.
[54] N. Grimaldi, F. Andrade, N. Segovia, L. Ferrer-Tasies, S. Sala, J. Veciana, N. Ventosa,
Lipid-based nanovesicles for nanomedicine, Chem. Soc. Rev. 45 (2016) 6520–6545.
[55] Y. Barenholz, Doxil® — the first FDA-approved nano-drug: lessons learned,
J. Contr. Release 160 (2012) 117–134.
[56] Y. Scindia, U. Deshmukh, P.R. Thimmalapura, H. Bagavant, Anti-alpha8 integrin
immunoliposomes in glomeruli of lupus-susceptible mice: a novel system for
delivery of therapeutic agents to the renal glomerulus in systemic lupus
erythematosus, Arthritis Rheum. 58 (2008) 3884–3891.
[57] E. Moallem, E. Koren, R. Ulmansky, G. Pizov, M. Barlev, Y. Barenholz, Y. Naparstek,
A liposomal steroid nano-drug for treating systemic lupus erythematosus, Lupus 25
(2016) 1209–1216.
[58] X. Guo, L. Wang, K. Duval, J. Fan, S. Zhou, Z. Chen, Dimeric drug polymeric
micelles with acid-active tumor targeting and FRET-traceable drug release, Adv.
Mater. 30 (2018).
[59] H. Zhang, R. Fu, C. Guo, Y. Huang, H. Wang, S. Wang, J. Zhao, N. Yang, Anti-dsDNA
antibodies bind to TLR4 and activate NLRP3 inflammasome in lupus monocytes/
macrophages, J. Transl. Med. 14 (2016) 156.
[60] L. Diao, J. Tao, Y. Wang, Y. Hu, W. He, Co-delivery of dihydroartemisinin and
HMGB1 siRNA by TAT-modified cationic liposomes through the TLR4 signaling
pathway for treatment of lupus nephritis, Int. J. Nanomed. 14 (2019) 8627–8645.
9
Biomedical Technology 4 (2023) 1–10
[61] N. Xu, J. Li, Y. Gao, N. Zhou, Q. Ma, M. Wu, Y. Zhang, X. Sun, J. Xie, G. Shen, et al.,
Apoptotic cell-mimicking gold nanocages loaded with LXR agonist for attenuating
the progression of murine systemic lupus erythematosus, Biomaterials 197 (2019)
380–392.
[62] S.G. Tangye, C.S. Ma, R. Brink, E.K. Deenick, The good, the bad and the ugly - TFH
cells in human health and disease, Nat. Rev. Immunol. 13 (2013) 412–426.
[63] J. Zhang, Q. Guo, D. Dai, J. Yu, L. Wang, Z. Wu, H. Ding, N. Shen, Y. Duan,
Rapamycin-encapsulated costimulatory ICOS/CD40L-bispecific nanoparticles
restrict pathogenic helper T-B-cell interactions while in situ suppressing mTOR for
lupus treatment, Biomaterials 289 (2022), 121766.
[64] M.A. Grimaudo, A. Concheiro, C. Alvarez-Lorenzo, Nanogels for regenerative
medicine, J. Contr. Release 313 (2019) 148–160.
[65] M. Look, E. Stern, Q.A. Wang, L.D. DiPlacido, M. Kashgarian, J. Craft, T.M. Fahmy,
Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus
erythematosus in mice, J. Clin. Investig. 123 (2013) 1741–1749.
[66] J. Liu, X. Zhang, X. Cao, Dendritic cells in systemic lupus erythematosus: from
pathogenesis to therapeutic applications, J. Autoimmun. 132 (2022), 102856.
[67] M. Look, W.M. Saltzman, J. Craft, T.M. Fahmy, The nanomaterial-dependent
modulation of dendritic cells and its potential influence on therapeutic
immunosuppression in lupus, Biomaterials 35 (2014) 1089–1095.
[68] R. Phillips, CAR T cells induce drug-free SLE remission, Nat. Rev. Rheumatol. 18
(2022), 671-671.
[69] A. Mullard, FDA approves first CAR T therapy, Nat. Rev. Drug Discov. 16 (2017),
669-669.
[70] X. Jin, Q. Xu, C. Pu, K. Zhu, C. Lu, Y. Jiang, L. Xiao, Y. Han, L. Lu, Therapeutic
efficacy of anti-CD19 CAR-T cells in a mouse model of systemic lupus
erythematosus, Cell. Mol. Immunol. 18 (2021) 1896–1903.
[71] R. Kansal, N. Richardson, I. Neeli, S. Khawaja, D. Chamberlain, M. Ghani, Q-u-
a Ghani, L. Balazs, S. Beranova-Giorgianni, F. Giorgianni, et al., Sustained B cell
depletion by CD19-targeted CAR T cells is a highly effective treatment for murine
lupus, Sci. Transl. Med. 11 (2019), eaav1648.
[72] D. Mougiakakos, G. Kr€ onke, S. V€
olkl, S. Kretschmann, M. Aigner, S. Kharboutli,
S. B€oltz, B. Manger, A. Mackensen, G. Schett, CD19-Targeted CAR T cells in
refractory systemic lupus erythematosus, N. Engl. J. Med. 385 (2021) 567–569.
[73] W. Zhang, J. Feng, A. Cinquina, Q. Wang, H. Xu, Q. Zhang, L. Sun, Q. Chen, L. Xu,
K. Pinz, et al., Treatment of systemic lupus erythematosus using BCMA-CD19
compound CAR, Stem Cell Rev Rep 17 (2021) 2120–2123.
[74] A. Mackensen, F. Muller, D. Mougiakakos, S. Boltz, A. Wilhelm, M. Aigner, S. Volkl,
D. Simon, A. Kleyer, L. Munoz, et al., Anti-CD19 CAR T cell therapy for refractory
systemic lupus erythematosus, Nat. Med. 28 (2022) 2124–2132.
[75] R. Khatri, T. Linn, Pancreatic mesenchymal stem cells might protect β-cells, Nat.
Rev. Endocrinol. 18 (2022) 725–726.
[76] D. Wang, H. Zhang, J. Liang, H. Wang, B. Hua, X. Feng, G.S. Gilkeson, D. Farge,
S. Shi, L. Sun, A long-term follow-up study of allogeneic mesenchymal stem/stromal
cell transplantation in patients with drug-resistant systemic lupus erythematosus,
Stem Cell Rep. 10 (2018) 933–941.
[77] J. Liang, H. Zhang, B. Hua, H. Wang, L. Lu, S. Shi, Y. Hou, X. Zeng, G.S. Gilkeson,
L. Sun, Allogenic mesenchymal stem cells transplantation in refractory systemic
lupus erythematosus: a pilot clinical study, Ann. Rheum. Dis. 69 (2010) 1423–1429.
[78] A. Li, F. Guo, Q. Pan, S. Chen, J. Chen, H.F. Liu, Q. Pan, Mesenchymal stem cell
therapy: hope for patients with systemic lupus erythematosus, Front. Immunol. 12
(2021), 728190.
[79] N. Che, X. Li, L. Zhang, R. Liu, H. Chen, X. Gao, S. Shi, W. Chen, L. Sun, Impaired B
cell inhibition by lupus bone marrow mesenchymal stem cells is caused by reduced
CCL2 expression, J. Immunol. 193 (2014) 5306–5314.
[80] J. Xu, J. Chen, W. Li, W. Lian, J. Huang, B. Lai, L. Li, Z. Huang, Additive therapeutic
effects of mesenchymal stem cells and IL-37 for systemic lupus erythematosus,
J. Am. Soc. Nephrol. 31 (2020) 54–65.
[81] M. Desgres, P. Menasche, Clinical translation of pluripotent stem cell therapies:
challenges and considerations, Cell Stem Cell 25 (2019) 594–606.
[82] J. Galipeau, L. Sensebe, Mesenchymal stromal cells: clinical challenges and
therapeutic opportunities, Cell Stem Cell 22 (2018) 824–833.
[83] A.S. Abu Lila, H. Kiwada, T. Ishida, The accelerated blood clearance (ABC)
phenomenon: clinical challenge and approaches to manage, J. Contr. Release 172
(2013) 38–47.
[84] C.M. Hu, L. Zhang, S. Aryal, C. Cheung, R.H. Fang, L. Zhang, Erythrocyte
membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform,
Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 10980–10985.
[85] X. Hao, H. Zhang, R. Liu, J. Che, D. Zhang, J. Liang, L. Sun, Red blood cell
membrane functionalized biomimetic nanoparticles for systemic lupus
erythematosus treatment, Materials Today Advances 16 (2022).
[86] Q. Guo, C. Chen, Z. Wu, W. Zhang, L. Wang, J. Yu, L. Li, J. Zhang, Y. Duan,
Engineered PD-1/TIGIT dual-activating cell-membrane nanoparticles with
dexamethasone act synergistically to shape the effector T cell/Treg balance and
alleviate systemic lupus erythematosus, Biomaterials 285 (2022), 121517.
[87] I.K. Herrmann, M.J.A. Wood, G. Fuhrmann, Extracellular vesicles as a next-
generation drug delivery platform, Nat. Nanotechnol. 16 (2021) 748–759.
[88] Y. Fang, J. Ni, Y.S. Wang, Y. Zhao, L.Q. Jiang, C. Chen, R.D. Zhang, X. Fang,
P. Wang, H.F. Pan, Exosomes as biomarkers and therapeutic delivery for
autoimmune diseases: opportunities and challenges, Autoimmun. Rev. 22 (2022),
103260.
X. Hao et al.
[89] Y. Fei, Q. Liu, N. Peng, G. Yang, Z. Shen, P. Hong, S. Wang, K. Rui, D. Cui, Exosomes
as crucial players in pathogenesis of systemic lupus erythematosus, Journal of
Immunology Research 2022 (2022), 8286498.
[90] D. Sun, X. Zhuang, X. Xiang, Y. Liu, S. Zhang, C. Liu, S. Barnes, W. Grizzle, D. Miller,
H.G. Zhang, A novel nanoparticle drug delivery system: the anti-inflammatory
activity of curcumin is enhanced when encapsulated in exosomes, Mol. Ther. 18
(2010) 1606–1614.
10
Biomedical Technology 4 (2023) 1–10
[91] A. Ortega, O. Martinez-Arroyo, M.J. Forner, R. Cortes, Exosomes as drug delivery
systems: endogenous nanovehicles for treatment of systemic lupus erythematosus,
Pharmaceutics 13 (2021) 3.
[92] T. Fang, B. Li, M. Li, Y. Zhang, Z. Jing, Y. Li, T. Xue, Z. Zhang, W. Fang, Z. Lin, et al.,
Engineered cell membrane vesicles expressing CD40 alleviate system lupus
nephritis by intervening B cell activation, Small Methods (2023), e2200925.
[93] E.I. Buzas, The roles of extracellular vesicles in the immune system, Nat. Rev.
Immunol. (2022) 1–15.