Table 5. Articles on the outcomes of exosome treatment on the salivary glands of Sjögren’s syndrome animal models.

Study	Experimental target	Source of exosomes	Exosome volume	Exosome size	Exosome delivery method	Exosome content/ markers	Outcomes measured	Results
Xing et al. 2022	NOD female mice, positive control group with intragastric infusion of Hydroxychloroquine, negative control infused with PBS, treatment group had either LGMSCs or LGMSC-Exos	Human labial gland mesenchymal stem cells (LGMSCs)	50μg/mL in 200μL PBS of LGMSC-Exos or LGMSCs (1×10^6 in 200μL PBS)	Median 121 nm, range 80−497 nm	Intravenous on alternate days for 14 days	CD9, CD63, Psg101	Flow cytometry on splenic lymphocytes for CD19, CD27 and CD138. RNA isolation and qRT-PCR. Saliva flow rates, lymphocyte infiltration in submandibular glands.	Improved saliva flow rate & reduced lymphocytes in Exos group, similar saliva flow rates and lymphocyte infiltration between the LGMSC-Exos and LGMSC groups; reduced PRDMI (a gene regulating B cell differentiation) expression in PBMCs.
Kim et al. 2021	Mice model of primary SS, with female NOD mice over 4 months old	Human induced pluripotent stem cells from MSCs, exosomes were collected from early passage P5 and late passage P15 iMSCs	1.5×10^10 particles in 100μL PBS	50−300 nm	IV into tail vein twice a week for 2 weeks	CD9, CD63, CD81	Submandibular gland and serum collected for lymphocyte infiltration	P5 iMSC EVs led to significantly decreased lymphocyte infiltration but P15 iMSC EVs had minimal difference. Only P5 EVs decreased serum anti-Lo and anti-Ro52, decreased mRNA levels of Th1 and Th17 cells and increased regulatory cytokines IL−10 and TGF-b1.
Li et al. 2021	Female NOD and BALB/c mice. Positive control group treated with HCQ intragastrically and BMMSC injection into the tail vein, negative control group (PBS injection), treatment groups LGMSCs or LGMSC-Exos injection.	Human Labial gland mesenchymal stem cell exosomes (LGMSC-Exos)			Tail vein injection-LGMSC-Exos 50μ/mouse, or LGMSC 10^6/mouse	CD 9, CD 63, CD 81	Saliva flow rate, histological assessment of salivary gland, serum cytokines	LGMSC-Exos treated mice showed a significantly increased salivary flow rate by 1.4g/10min compared to control mice with PBS. Salivary gland lymphocyte infiltration was significantly reduced in the LGMSC and LGMSC-Exos groups compared to negative control.
Rui et al. 2021	Female C57BL/6 mice immunised with 200 μg of SG proteins via SC injection in the neck on day 0 and 7 and then booster injection on day 14, to stimulate ESS.	Olfactory ectodermal mesenchymal stem cells (C57BL/6 mice). Bone marrow mesenchymal stem cells (BMMSCs) from the tibia and femur of these mice.	60 μg/mL	50−150 nm	Two IV injection of 100 μg of OE-MSC-Exos or BM-MSC-Exos on days 18 and 25 after the first immunisation	CD9, CD63, IL−6, TLR4	Quality real time-PCR, saliva flow rates, histological analysis of submandibular glands for lymphocytic foci	Improvement in the saliva flow rates following OE-MSC-Exos or BM-MSC-Exos Rx by 120microL/15min. Reduced serum autoantibodies against SSA, M3R and SG antigens in the OE-MSC-Exos group compared to BM-MSC-Exos and control. Reduced histological scores of SG destruction in OE-MSC-Exos compared to BM-MSC-Exos.
Rui et al. 2022	Female C57BL/6 mice immunised with 200 μg of SG proteins via SC injection in the neck on day 0 and 7 and then booster injection on day 14, to stimulate ESS.	Olfactory ectodermal mesenchymal stem cells, from the nasal cavity of C57BL/6 mice	Not mentioned	Not tested	Intravenous exosomes injection-100 μg/mouse at 18- and 25-days post first immunisation	PD-L1	Saliva flow rate, salivary gland histology, Serum antibodies.	OE-MSC-Exos treated mice had smaller spleens, cervical LNs; significantly restored saliva flow by 80microL/15min with OE-MSC-Exos treatment at 35 days; reduced serum anti-SG, anti-M3R and anti-SSA
Chu et al. 2023	14-week-old NOD mice	Human exfoliated deciduous teeth		137 + / −6.2nm	50μg in 25μL of PBS exosomes injected in submandibular gland	CD9, CD63 and HSP70	Stimulated saliva flow, lymphocyte infiltration in SMGs, TUNEL staining for apoptotic cells, capase− 1 activity, ROS levels	7 weeks after exosome treatment, the saliva flow rate was increased from 38 in age matched NOD and PBS groups to 55μL/min/100g Reduced lymphocyte foci in treated SMG, reduced apoptotic cells, cleaved caspase−3 and decreased levels of ROS
Du et al. 2023	7- and 14-week-old NOD mice and age matched BALB/c mice	Human exfoliated deciduous teeth		126.5 + /−5.7	50μ g in 25μ L of PBS exosomes injected in submandibular gland or infused through intraoral duct orifice(OD) of SMG at 14 weeks age	CD9,CD63, CD81, HSP70	Stimulated saliva flow rate, lymphocyte infiltration of SMG with focus score and ratio index	Saliva flow rate improved from 22 to 55μL/min/100g in the NOD mice at 21 weeks compared to Exosomes group at 21 weeks. Focus score and ratio score of lymphocyte infiltration were both decreased in the exosomes group compared to age matched untreated and PBS treated groups.
Hu et al. 2023	NOD 2 female mice, 6 positive control with hydroxychloroquine gastric infusion, 6 negative control with PBS gastric infusion, 6 treatment group	Human dental pulp stem cell	5, 20 and 80μg/mL	30−150 nm	Weekly intravenous injections for 10 weeks	CD63, ALIX, TSG101	Saliva flow rate, immunohistochemistry and immunofluorescence, ELISA of venous blood for anti-SSA/Ro, anti-SSB/La	Increased saliva flow rate by 0.2g/10min, reduced lymphocyte foci in salivary glands, increased AQP5 and GPER expression; HCQ and DPSC-Exos downregulated anti-SSA/Ro and anti-SSB/La serum levels
Ogata et al. 2023	Female NOD mice, treatment group given exosomes, control group given PBS	iPSC with different graded concentrations of secreted HGF and TGF-b1	300μ/mL	200 nm	30 μg delivered once IV through the tail vein	CD9, CD81	Saliva flow rates, serum anti-SSA antibody, salivary gland inflammatory cell infiltration, mRNA of cytokines produced in the salivary glands	iPS-EVs (higher HGF and TGF-b1) improved saliva flow rates (17.5μl/15min), PBS group (10.5μl/15min) and the iPS-EVs (lower HGF and TGF-b1) 13μl/15min; decreased salivary gland inflammatory cell infiltration;
Zhao et al. 2023	4-month-old female NOD.B10.H2 mice, model of primary SS	Human induced pluripotent stem cells from MSCs, early passage PD15 and late passage PD45	1.5×10^10 particles in 100μL PBS		IV infusion of EVs dyed with DiR (near infrared fluorescent dye)		Mice imaged in vivo 1, 3 and 24hrs after injection, major organs visualised for presence of EVs	decreased serum anti-SSA, IL−6 and TNF-a; increased anti-inflammatory cytokines IL−10 and TGF-b1 DiR was strongest in the liver and spleen, but not present in cervical lymph nodes or SMG collected at 24hrs after injection. miR− 125b inhibitors incubated ageing iMSCs reduced leucocyte infiltrate in SMG, not with ageing EVs (with miR-125b acitivty).
Zhou et al. 2023	ESS mice model made by immunising C57BL/6 mice with SG proteins on day 0, 7 and a booster on day 14	Myeloid derived suppressor cells from the spleen of tumour bearing C57BL/6 mice		50−150 nm	100 μg/mouse delivered IV on days 18 and 25 after first immunisation	CD63, CD19, TSG101, but not calnexin	Saliva flow rates, serum autoantibodies against SG antigen, ANA, anti-M3R, size of the spleen, cervical lymph nodes and salivary glands	Improved saliva flow rate by 75microL/15min with exosomes compared to ESS alone. Reduced serum level of autoantibodies against SG antigen, ANA and anti-M3R antibodies; smaller sized spleen, cervical lymph nodes and salivary glands in the exosome treated mice

NOD-Non-Obese Diabetoc, PBS − Phosphate Buffer Solution, qRT-PCR- Qualitative Reverse Transcription Polymerase Chain Reaction, PBMC- Peripheral Blood Mononuclear Cell, HCQ- Hydroxychloroquine, MSC − Mesenchymal Stem Cell, BMMSC − Bone Marrow MSC, SG − Salivary Gland, SC − Subcutaneous, LN − lymph node, SMG − Submandibular Gland, TUNEL - terminal deoxynucleotidyl transferase dUTP nick end labeling, ROS − Reactive Oxygen Species, ELISA - Enzyme-Linked Immunosorbent Assay, AQP5 − Aquaporin 5, GPER − G-protein coupled estrogen receptor, iPSC − induced Pluripotent Stem Cells, HGF- Hepatocyte Growth Factor, SS- Salivary Gland, ESS − Experimental Sjögren’s Syndrome, ANA − Anti-nuclear Antibody