Table 1 Therapeutic exosomes for treatment of RA

Mouse bone marrow MSC

FLS

Bare

N/A

N/A

Wistar Rat RA model

TNF-α, IL-6, IL-8 ↓

FLSs proliferation ↓

Bax, PUMA, cytochrome C ↑

Negatively target cyclin I and activation of ATM/ATR/p53 signaling pathway

Arthritis score ↓

[155]

Human bone marrow MSC

FLS

Bare

N/A

N/A

CIA

IL-1β, IL-6, IL-8 ↓

Negatively target CXCL9 and suppression of activation, migration, and invasion of FLSs

[156]

Human gingival MSC

T cell

Bare

N/A

N/A

CIA

CD4⁺IL-10⁺ T cells, IL-10 ↑

CD4⁺IFNγ⁺Th1, CD4⁺IL-17A⁺Th17, IFN-γ, IL-17A ↓

Incidence of arthritis and bone erosion ↓

IL-17RA-Act1-TRAF6-NF-κB signaling pathway ↓

Arthritis score ↓

[157]

Human umbilical cord MSC

T cell

Bare

N/A

N/A

N/A

(RA patient)

Regulation of imbalance of Treg/Th17

IL-17 ↓

TGF-β ↑

[158]

Human umbilical cord MSC

T cell

Bare

N/A

N/A

CIA

RORγt ↓, Foxp3 ↑

Th17 cells, IL-17 ↓

Treg cells, IL-10, TGF-β ↑

Arthritis score ↓

[159]

Bovine milk

T cell

Bare

N/A

N/A

Polyarthritis (IL-1Ra^−/−), CIA

TNF-α, MCP-1 ↓

Foxp3⁺ Tregs, TGF-β ↑

Delay the onset of IL-1Ra^−/− polyarthritis and CIA

Regulation of Th1, Th2, Treg, and Th17 cells in both gut and spleen

[160]

Granulocytic-myeloid derived suppressor cell from CIA mice

T cell

Bare

N/A

N/A

CIA

Symptoms of RA ↓

Th1, Th17 cells, IFN-γ, IL-17A ↓

Th1↓via exosomal miR-29a-3p

Th17 ↓ via exosomal miR-93-5p

Arthritis score ↓

[161]

Mouse bone marrow MSC

T cell

B cell

Bare

N/A

N/A

CIA,

DTH

CD4⁺IL-10⁺ Tr1, CD4⁺CD25⁺Foxp3⁺ Treg ↑

CD8⁺IFNγ⁺ Cytotoxic T cells, CD4⁺IFNγ⁺ Th1 ↓

Plasmablast differentiation ↓

IL-10⁺ Breg ↑

Arthritis score ↓

[162]

Granulocytic-myeloid derived suppressor cell from tumor-bearing mice

B cell

Bare

N/A

N/A

CIA

Symptoms in CIA ↓, IgG and anti-CII antibody ↓

IL-10⁺ B cells ↑, plasma cells and follicular Th cells ↓

Phosphorylation of GSK-3β ↑ via exosomal PGE2

Arthritis score ↓

[163]

Human MSC

FLSs

Genetic manipulation

miRNA overexpression

miR-124a

N/A

MH7A, RA FLSs cell lines, proliferation ↓

Cell cycle arrest at G0/G1 phase

Migration and invasion of MH7A ↓

Apoptosis of MH7A ↑ (Bax, Bid, Bim, Bcl-2, Caspase-3, Caspase-9 ↑)

[164]

Rat bone marrow MSC

FLS

Genetic manipulation

miRNA overexpression

miR-192-5p

CIA

RAC2 ↓ via exosomal miR-192-5p

TNF-α, IL-1β, PGE2, NO, iNOS↓

Arthritis index ↓

[165]

Mouse bone marrow MSC

FLS

Genetic manipulation

miRNA overexpression

miR-150-5p

CIA

MMP14, VEGF↓via exosomal miR-150-5p

Migration and angiogenesis of FLSs ↓

Arthritis index ↓

[166]

Human embryonic kidney 293 cell (HEK 293)

Macrophage

Genetic manipulation

Protein overexpression

IL-4

CIA

Localication of IL4Rα to early endosome ↑

M1 marker (TNF-α, CXCL10, iNOS, NO)↓

M2 marker (Arg, CD206) ↑

Arthritis index ↓

[167]

Bone marrow-derived DC

DC

Genetic manipulation

Protein overexpression

FasL

CIA,

DTH

Internalize into CD11c⁺ DCs

FasL-dependent effect

MHC II-dependent effect

Immunosuppressive in allogeneic mice

Arthritis index ↓

[102]

Bone marrow-derived DC

DC,

Macrophage,

T cell

Genetic manipulation

Protein overexpression

IL-4

CIA,

DTH

Internalize into CD11c⁺ DCs, F4/80⁺ macrophages

Partially FasL-dependent effect

MHC-dependent effect

Effect on CD11c⁺ DCs, CD3⁺ T cells

Arthritis index ↓

[103]

Bone marrow-derived DC

DC

Genetic manipulation

Protein overexpression

IDO,

CTLA-4Ig

CIA,

DTH

B7 molecules (CD80, CD86)-dependent effect

IDO-mediated depleted tryptophan-dependent effect

Arthritis index ↓

[104]

Bone marrow-derived DC

T cell

Genetic manipulation

Preconditioning

DC differentiation

IL-10

CIA,

DTH

T cell proliferation ↓ in vitro

MHC II-dependent effect

Immunosuppressive with intact morphology

Arthritis index ↓

[80]

Macrophage

Macrophage

Preconditioning

Macrophage differentiation

IL-4

CIA

Favorable uptake into macrophages

iNOS, TNF-α, IL-6 ↓, and Arg-1, CD163, TGF-β, IL-10 ↑ in reprogrammed M2

In situ reprogramming of M1 to M2 in synovial tissue

Arthritis index, bone erosion ↓

[168]

Human bone marrow MSC

T cell

Preconditioning

Hypoxic,

Normoxic,

Pro-inflammatory

O₂ portion,

Pro-inflammatory cocktail

AIA

Arthritis index, joint swelling ↓

Synovial infiltrate ↓ (only in EV-NormO₂)

Th17 ↓ (only in EV-2%O₂, EV-NormO₂)

Treg:Th17 ↑ (only verified in EV-NormO₂)

[169]

Adipose-derived stem cell

Macrophage

Metabolic glycoengineering-mediated bioorthogonal click chemistry

Surface modification

Dextran sulfate

CIA

Cellular uptake into activated macrophages ↑

Accumulation into inflamed joints via SR-A binding ↑

Reprogramming M1 to M2 (iNOS ↓, CD206 ↑)

Reprogramming M1 to M2 ↓ via miRNA inhibitor

Arthritis index ↓, Synovial infiltration ↓

IFN-γ, TNF-α, IL-6, G-CSF, GM-CSF, IL-1β, IL-17A ↓

IL-4, IL-10 ↑

[122]

Human neutrophil

Arthritic cartilage,

Chondrocyte

Sonication

Antibody incorporation

Anti-ROS-CII,

Anti-ROS-CII-vIL-10,

Anti-TNFα

AIA

Specific localization in arthritic joints

Pro-inflammatory gene (Tnf, Il-1β, IL-6, Mmp13, Adamts5) ↓

Anti-inflammatory gene (In-4, IL-10, Sox9, Acan, Col2a1) ↑

Complete resolution of joint swelling

[170]

Macrophage

Chondrocyte

Sonication

Encapsulation

EGCG

CIA

HIF-1α ↓

Chondrocyte apoptosis ↓ (Cytochrome C, Caspase-3, Caspase-9, Bax, Bcl-2↓)

Cartilage type II collagen ↑

Arthritis score ↓

[171]

Platelet

DC,

Macrophage,

T cell

Incubation

Encapsulation

Berberine

CIA

Macrophages, DCs activation ↓

Accumulation in inflamed joints

CD45⁺ cells, T cells, macrophages, DCs ↓

Bone erosion, arthritic score ↓

Regulation of cytokines

[172]

Adipose human MSC

Synoviocyte

Incubation

Encapsulation

Curcumin

N/A

Acidic pH triggered faster Curcumin release

Apoptosis of LPS-stimulated synovial cells ↑

IL-6, TNF-α, MMP-1, PGE2 ↓

[173]

Macrophage

Macrophage

Electroporation

Hydrophobic insertion

Encapsulation,

Surface modification

Dexamethasone,

FA-PEG-Chol

CIA

Acidic pH triggered faster Dexamethasone release

Cellular uptake into activated macrophage ↑

TNF-α and IL-1β ↓, IL-10 ↑ in vitro and in vivo

Accumulation in the joints ↑

Bone erosion ↓

No hepatotoxicity

[174]

DCs

DC,

T cell

Preconditioning,

Hydrophobic insertion

DC differentiation,

Surface modification

IL-10,

DSPE-TK-mPEG

CIA

Selective cellular uptake into mature DCs via cleavage of ROS-sensitive TK linker on exosomal surface

CD40, TNF-α, IL-6, CD4⁺ T cells ↓

Prolonged blood circulation, accumulation in joint ↑

IL-16 ↓, TGF-β and Treg ↑

[153]

Neutrophil

FLS,

Chondrocyte

Macrophage

Preconditioning,

Bioorthogonal click chemistry

Protein upregulation,

uPB incorporation on exosomal surface

LPS,

uPB

CIA

Cellular uptake into activated FLS, chondrocyte, and macrophage ↑

Apoptosis of activated FLS, chondrocyte, and macrophage ↓

Protection against oxidative stress via SOD-2 mimics

Accumulation into inflamed joints↑

Treg ↑ and Th1 ↓

Arthritis index, bone erosion ↓

[175]

Macrophage

Macrophage

Preconditioning,

Transfection,

Electroporation

Macrophage differentiation,

Protein expression,

Encapsulation

IL-4,

IL-10 pDNA,

BSP

CIA

Macrophage polarization from M1 to M2

Enhanced cellular uptake into M1

iNOS, IL-12 ↓ and CD206, Arg-1 ↑

Accumulation into arthritic joints ↑

Arthritis index ↓

Serum IL-1β, TNF-α ↓ and IL-10, IL-4 ↑

No hepatotoxicity

[176]

Macrophage

Macrophage

Electroporation,

Exogenous stimuli

Encapsulation, Enhancement of targeting effect

IL-10,

US

CIA

Cellular uptake into LPS-activated macrophage upon US irradiation ↑

Arthritis index, bone erosion ↓

IL-6, TNF-α ↓

CD86/CD206 ratio↓(CD206↑)

[177]

Macrophage

Macrophage

Chemical binding,

Ultrasonication

Enhanced cellular uptake,

Encapsulation

Polyarginine peptide, Curcumin

CIA,

SCI

Cellular uptake into M1 macrophage ↑

Accumulation into inflamed joints ↑

CD206 ↑

Bone erosion, arthritic score ↓

[178]