Potential of Exosomes as Cell-Free Therapy in Articular Cartilage Regeneration: A Review

Figures & data

Figure 1 Flow diagram of article selection process.

Table 1 Summary of Risk of Bias Analysis Using SYRCLE Tool

References	Selection Bias			Performance Bias		Detection Bias		Attrition Bias	Reporting Bias
	Sequence Generation	Baseline Characteristics	Allocation Concealment	Random Housing	Blinding	Random Outcome Assessment	Blinding	Incomplete Outcome Data	Selective Outcome Reporting
Zhang et al^Citation68	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Cosenza et al^Citation74	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Liu et al^Citation58	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Tao et al^Citation60	Unclear	Low risk	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Wang et al^Citation61	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Zhu et al^Citation72	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Mao et al^Citation59	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Wang et al^Citation79	Unclear	Low risk	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Zhang et al^Citation69	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Chen et al^Citation73	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Liu et al^Citation82	Unclear	Low risk	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Wu et al^Citation64	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Zhang et al^Citation70	Unclear	Low risk	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Zheng et al^Citation81	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Chen et al^Citation56	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
He et al^Citation75	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Jin et al^Citation76	Unclear	Low risk	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Jin et al^Citation57	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Liang et al^Citation77	Unclear	Low risk	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Liu et al^Citation78	Unclear	Low risk	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Qiu et al^Citation83	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Wong et al^Citation63	Unclear	Low risk	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Yan and Wu^Citation66	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Zavatti et al^Citation67	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Zhang et al^Citation84	Unclear	Low risk	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Zhou et al^Citation71	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Wang et al^Citation80	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Wang et al^Citation62	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk
Yan et al^Citation65	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Unclear	Low risk

Table 2 Cell Sources, Exosome Isolation, and Characterization

References	Cell Sources	Cell Types	Exosome Isolation	Exosome Characterization
Zhang et al^Citation68	Human	HuES9 ESC-MSCs	Size fractionation and TFF Exosomes were stored at −20 °C until use	NTA: Homogenously sized with modal size of 100 nm Western blot: Positive for CD81, ALIX, and TSG101 RNA detection: Majority less than 300 nucleotides
Cosenza et al^Citation74	Murine	BM-MSCs from C57BL/6 mice	Ultracentrifugation	DLS: 96 nm NTA: 112 ± 6.6 nm Flow cytometry: Positive for CD9 and CD81
Liu et al^Citation58	Human	iPSC (iPSC-01)-MSCs	Ultracentrifugation and ultrafiltration	TEM: Spherical morphology; 30 to 60 nm TRPS: 50 to 150 nm Western blot: Positive for CD9, CD63, and CD81
Tao et al^Citation60	Human	Normal SM-MSCs and miR-140-5p-overexpressing SM-MSCs from knee joint synovial membrane tissue of 30 to 35 years old donors	Ultrafiltration and ultracentrifugation on 30% sucrose/D2O cushion Used freshly	TEM: Hollow spherical microvesicles DLS: 30 to 150 nm Western blot: Positive for CD63, CD9, CD81, and ALIX RT-qPCR: Increased miR-140-5p expression level in miR-140-5p overexpressed SM-MSC-Exos
Wang et al^Citation61	Human	Male H1 ESC-MSCs	Ultracentrifugation Exosomes were stored in PBS at −80 °C	TEM: Round lipid bilayer vesicles; 38 to 169 nm Western blot: Positive for CD63 and CD9
Zhu et al^Citation72	Human	iPSC (C1P33)-MSCs	Ultrafiltration The exosomes aliquot was stored −80 °C or used freshly	TEM: Cup or round-shaped TPRS: 50 to 150 nm Western blot: Positive for CD9, CD63, and TSG101
	Human	SM-MSCs from 3 donors (2 males and 1 female, age range 22 to 28 years)	Ultrafiltration The exosomes aliquot was stored −80 °C or used freshly	TEM: Cup or round-shape TPRS: 50 to 150 nm. Western blot: Positive for CD9, CD63, and TSG101
Mao et al^Citation59	Human	Normal BM-MSCs and miR-92a-3p-overexpressing BM-MSCs from 6 donors (3 males and 3 females, ranged of 32 to 38 years old)	Ultracentrifugation	TEM: Cup-shaped or round morphology; 50 to 150 nm NTA: 50 to 150 nm. Western blot: Positive for CD9, CD63, CD81, and HSP70
Wang et al^Citation79	Murine	Normal MSCs, TGF-β1 stimulated MSCs and miR-135b inhibited MSC from SD rats	Exosome extraction kit	TEM: Hollow-spherical morphology Western blot: Positive for CD63, CD9, and CD81; higher CD81 and ALIX levels in TGF-β1-MSC-Exos RT-qPCR: Increased miR-135b expression level in TGF-β1-MSC-Exos
Zhang et al^Citation69	Human	Immortalized E1-MYC 16.3 ESC-MSCs	Size fractionation and TFF Exosomes were stored at −20 °C until use	Size determination: Homogenously sized particles; 100 nm model size Western blot: Positive for CD81, ALIX, and TSG101 Flotation density: 1.10 to 1.19 g/mL
Chen et al^Citation73	Murine	BM-MSCs from articular cartilage from femoral condyles and tibial plateau of C57BL/6 mice	Ultrafiltration and ultracentrifugation on 30% sucrose/D2O cushion	TEM: Hollow spherical vesicles DLS: 40 to 110 nm in diameter Western blot: Positive for TSG101, CD9, and CD63
Liu et al^Citation82	Rabbit	PRP isolated from whole blood of New Zealand white rabbits	Membrane-based affinity binding step using exoEasy Maxi Kit Exosomes were stored at −80 °C until used	TEM: Round-shaped morphology NTA: 145.6 ± 50.4 nm Western blot: Positive for CD9, CD63, CD81, and HSP101
Wu et al^Citation64	Human	IPFP-MSCs from patients with primary knee OA	Precipitation (ExoQuick reagent kit) or ultrafiltration Exosomes were stored at −80 °C for further use	No significant differences between exosomes isolated from precipitation and ultrafiltration TEM: Sphere-shaped bilayer membrane structure about 100 nm in diameter NTA: 121.9 nm Western blot: Positive for CD81, CD9, and CD63 Flow cytometry with CiO-labeling: 30 nm to 150 nm
Zhang et al^Citation70	Human	Immortalized E1-MYC 16.3 ESC-MSCs	Size fractionation and TFF Exosomes were stored at −20 °C until use	Size determination: 100 to 200 nm Western blot: Positive for CD81, ALIX, and TSG101 Flotation density: 1.10 to 1.19 g/mL
Zheng et al^Citation81	Murine	Primary chondrocytes from knee articular cartilage of 5 to 6 days old C57BL/6 mice cultured in standard or inflammatory environment (degenerative chondrocytes)	Ultrafiltration and ultracentrifugation with 30% sucrose/D2O	TEM: Hollow and spherical-like morphology DLS: 40 to 110 nm Western blot: Positive for TSG101, CD9, and CD63 Mass spectrometry: 2409 and 2077 proteins were identified in primary chondrocytes and degenerative chondrocytes, respectively
Chen et al^Citation56	Human	Normal BM-MSCs and miR-136-5p-overexpressed BM-MSCs from femur bone marrow of traumatized patients	Ultrafiltration and ultracentrifugation with 30% sucrose/D2O	TEM: Hollow spherical microvesicles DLS: 50 to 150 nm Western blot: Positive for CD63, CD9, CD81, and ALIX; but very low TSG101 RT-qPCR: Upregulated miR-136-5p expression level in miR-136-5p overexpressed BM-MSC-Exos
He et al^Citation75	Murine	BM-MSCs from SD rats	Ultracentrifugation	TEM: Oval in shape DLS: 153 nm Western blot: Positive for flotillin-1, TSG101, and CD63; negative for calnexin
Jin et al^Citation76	Murine	Normal BM-MSCs and miR-9-5p overexpressed BM-MSCs	Ultracentrifugation Exosomes were stored at −80 °C	TEM: Round or tea-shaped with outer membrane; 40 to 100 nm Western blot: Positive for CD9, TSG101, and CD63; negative for calnexin
Jin et al^Citation57	Human	Normal BM-MSCs and miRNA-26a-5p overexpressed-BM-MSCs from ilium of healthy volunteers	Precipitation (ExoQuick-TC reagent kit)	TEM: Round or oval-shaped; 30 to 100 nm DLS: 50 to 100 nm Western blot: Positive for CD63, Hsp70, and CD90 RT-qPCR: Upregulated miR-26a-5p expression level in miR-26a-5p overexpressed BM-MSC-Exos
Liang et al^Citation77	Murine	CAP-Lamp2b dendritic cells	Ultracentrifugation Exosomes were stored at −80 °C miR-140 mimic is introduced into exosomes by electroporation	TEM: Cup-shaped morphology; 40 to 200 nm NTA: 40 to 200 nm Western blot: Positive for CD63 and CD9 Confocal microscope: Fluorescence signals of CAP-GFP-Exos
Liu et al^Citation78	Murine	Normal BM-MSCs from SD rats and BM-MSCs treated with kartogenin	TFF and HPLC Exosomes were stored at −80 °C	TEM: Cup or round-shaped morphology NTA: 50 to 200 nm Western blot: Positive for CD63 and CD81
Qiu et al^Citation83	Not reported	Normal BM-MSCs and curcumin pre-treated BM-MSCs	Ultrafiltration	TEM: Round-shaped morphology; 50 to 150 nm Western blot: Positive for CD9, CD63, and CD81
Wong et al^Citation63	Human	E1-MYC 16.3 ESC-MSCs	Size fractionation and TFF Exosomes were stored at −20 °C until use	Size determination: 100 to 200 nm Western blot: Positive for CD81, ALIX, and TSG101
Yan and Wu^Citation66	Human	UC-MSCs cultured in 2D and 3D (hollow-fiber bioreactor)	Ultracentrifugation Exosomes were stored at −80 °C until used	TEM: Cup-shaped morphology NTA: 120 nm Western blot: Positive for CD63, CD81, and TSG101; negative for calnexin
Zavatti et al^Citation67	Human	AFSCs from pregnant women (mean age of 35.7) between the 16th and 17th weeks of gestation	Precipitation (total exosome isolation solution)	Western blot: Positive for CD9, CD63, CD81, and Rab5
Zhang et al^Citation84	Not reported	BM-MSCs	Ultrafiltration and ultracentrifugation with sucrose cushion Exosomes were stored at −80 °C or used freshly	TEM: Cup-like shape NTA: 140 nm Western blot: Positive for CD63, CD81, and CD9; negative for cerulean
Zhou et al^Citation71	Human	Polydactyly BM-MSCs	Precipitation (total exosome isolation kit)	TEM: 30 to 150 nm Western blot: Positive for CD63 and CD9
	Human	BM-MSCs	Precipitation (total exosome isolation kit)	TEM: 30 to 150 nm Western blot: Positive for CD63 and CD9
Wang et al^Citation80	Murine	OA serum from OA mice and sham serum from sham mice	Norgen’s proprietary resin-based purification (Serum Exosome Purification Mini Kit) ATF4-OA-Exos were constructed by introducing ATF4 mRNA into OA-Exos through electroporation.	TEM: Spherical-shaped morphology NTA: 0 to 150 nm Western blot: Positive for ALIX and CD63 RT-qPCR: Highest expression level of ATF4 in ATF4-OA-Exos, followed by OA-Exos and sham-Exos
Wang et al^Citation62	Human	Normal SM-MSCs and miR-155-5p-overexpressing SM-MSCs	Not reported	TEM: Cup-shaped morphology NTA: 100 to 120 nm Western blot: Positive for CD63 and CD81; negative for TFIIB RT-qPCR: 60-fold higher miR-155-5p expression in miR-155-5p overexpressed SM -MSC-Exos compared to SM-MSC-Exos
Yan et al^Citation65	Human	UC-MSCs cultured in static environment and rotary cell culture system	Ultracentrifugation Exosomes were stored at −80 °C	TEM: Cup-shaped morphology NTA: 120 nm Western blot: Positive for CD63, CD81, and TSG101; low calnexin RT-qPCR: Increased lncRNA H19 expression level in exosomes collected from cells cultured in rotary cell culture system

Abbreviations: AFSC, amniotic fluid stem cell; BM-MSC, bone marrow-derived mesenchymal stem/stromal cell; CAP-Lamp2b, chondrocyte-affinity peptide-lysosome-associated membrane glycoprotein 2b; D2O, deuterium oxide; DLS, dynamic light scattering; ESC-MSC, embryonic stem cell-derived mesenchymal stem/stromal cell; Exo, exosome; IPFP-MSC, infrapatellar fat pad-derived mesenchymal stem/stromal cell; iPSC-MSC, induced pluripotent stem cell-derived mesenchymal stem/stromal cell; lncRNA, long non-coding RNA; miR, microRNA; MSC, mesenchymal stem/stromal cell; NTA, nanoparticle tracking analysis; PBS, phosphate-buffered saline; PRP, platelet-rich plasma; RT-qPCR, reverse transcription quantitative polymerase chain reaction; SD rat, Sprague Dawley rat; SM-MSC, synovial membrane-derived mesenchymal stem/stromal cell; TEM, transmission electron microscopy; TFF, tangential flow filtration; TGF-β1, transforming growth factor beta 1; TPRS, tunable resistive pulse sensing; UC-MSC, umbilical cord-derived mesenchymal stem/stromal cell.

Table 3 Summary of Efficacy and Safety Findings

References	Animal Models	Method of Delivery	Treatment Groups	Euthanasia	Efficacy Outcome			Safety Outcome
					Macroscopic and Functional Analysis	Imaging	Histological and Biochemical Analysis
Zhang et al^Citation68	SD rats Surgically induced OCD	Multiple intra-articular injections after surgery and thenceforth weekly	1. Exo group: 100 µg/100 µL of ESC-MSC-Exos 2. Contralateral control: 100 µL PBS 3. Un-operated control	Week 6 or 12 post-surgery	● Exo group demonstrated almost complete neotissue filling with good surface regularity and complete integration of neotissue with surrounding cartilage by 12 weeks	Not reported	● Exo group exhibited almost complete regeneration and bonding of cartilage and underlying subchondral bone after 12 weeks ● Distinctly higher modified O’Driscoll histological scores in the Exo group ● Exo group showed hyaline cartilage formation with high amount of GAG, Col II, and low amount of Col I	No detrimental responses were observed in all animals
Cosenza et al^Citation74	C57BL/6 mice Collagenase-induced OA	Single intra-articular injection at day 7 after OA induction	1. Cell group: 2.5×10^5 BM-MSCs/5 µL 2. MP group: 500 ng/5 µL of BM-MSC-microvesicles 3. Exo group: 250 ng/5 µL of BM-MSC-Exos 4. OA group 5. Healthy control	Day 42 post-collagenase induction	Not reported	● CLSM showed structural improvement in articular cartilage which comparable with healthy control group in all treatment groups ● µCT showed higher bone volume, lower bone degradation, lower osteophyte formation and lower calcification of menisci and ligaments in all treatment groups compared to the OA group	● Exo group showed the greatest improvement with the lowest OA scores	Not reported
Liu et al^Citation58	New Zealand rabbits Surgically created OCD	Scaffold implantation or single intra-articular injection immediately after surgery	1. EHG group: 20 µL in situ formed EHG tissue patch containing 1 × 10^11/mL iPSC-MSC-Exos 2. HG group: 20 µL in situ formed HG tissue patch 3. Pre-EHG group: 20 µL in vitro preformed EHG containing 1 × 10^11/mL iPSC-MSCs-Exos 4. Inj-Exo group: 20 µL of 1 × 10^11/mL iPSC-MSCs-Exos suspension 5. OA group: Saline rinsing	Week 12 post-surgery	● EHG group showed the best repair with smooth surface with white regenerated tissue fully filled the defects and integrated with surrounding cartilage	● OCT displayed uniform and well-organized articular cartilage structure in EHG group	● EHG group has the highest ICRS score and the neotissue was almost entirely hyaline cartilage (strong safranin O and Col II staining, weak Col I staining)	Not reported
Tao et al^Citation60	SD rats Surgically induced OA	Multiple intra-articular injections on the first day of week 5 to 8 after surgery	1. Exo group: 100 µL of 10^11 SM-MSC-Exos particles/mL 2. Exo-miR-140-5p group: 100 µL of 10^11 miR-140-5p overexpressed SM-MSC-Exos particles/mL 3. OA group: Saline 4. Healthy control: Saline	Week 12 post-surgery	Not reported	Not reported	● Exo-miR-140-5p group showed the lowest OARSI assessment scores ● Significant increased chondrocyte count, higher Col II and aggrecan expression, and lower Col I in the Exo-miR-140-5p group compared to the Exo and OA groups	No adverse events occurred
Wang et al^Citation61	C57BL/6 J mice DMM induced OA	Intra-articular injections at week 4 after surgery (once for Cell and Cell-OA group; multiple injections every 3 days for 4 weeks for Exo and Exo-OA group)	1. Cell group: 5 μL of 1×10^6 ESC-MSC suspension 2. OA group: 5 µL of PBS 3. Sham control 1. Exo group: 5 µL ESC-MSC-Exos 2. OA group: 5 µL of PBS 3. Sham control	Week 8 post-surgery	Not reported	Not reported	● Exo group exhibited similar regenerative effect as Cell group. ● Exo group revealed milder OA pathology compared to the OA group which was concomitant with lower OARSI scores and stronger Col II staining and weaker ADAMTS5 and aggrecan neoepitope staining	Not reported
Zhu et al^Citation72	C57B/L10 mice Collagenase-induced OA	Multiple intra-articular injections on day 7, 14 and 21 after collagenase administration	1. iPSC-MSC-Exo group: 8 µL of 1×10^10 particles/mL iPSC-MSC-Exos 2. SM-MSC-Exo group: 8 µL of 1×10^10 particles/mL SM-MSC-Exos 3. OA group: 8 µL of PBS 4. Normal control: 8 µL of PBS	Day 28 post-collagenase induction	● No significant differences in ICRS macroscopic analysis scores among the normal, iPSC-MSC-Exo and SM-MSC-Exo groups, but significant higher than the OA group	Not reported	● Neotissue of iPSC-MSC-Exo group presented smooth cartilage, regular cellular organization and normal proteoglycan content that similar to control group; SM-MSC-Exo exhibited moderate surface irregularity, superficial fibrillation in neotissue and lower proteoglycan in cartilage, but the results were better compared to the OA group ● No significant differences in OARSI scores between the iPSC-MSC-Exo and normal group, but notable lower than the SM-MSC-Exo and OA groups ● More intense Col II staining in the iPSC-MSC-Exo group compared to the SM-MSC-Exo group	Not reported
Mao et al^Citation59	C57B/L10 mice Collagenase-induced OA	Multiple intra-articular injections on day 7, 14 and 21 after collagenase administration	1. Exo group: 15 µL of 500 µg/mL BM-MSC-Exos 2. Exo-miR-92a-3p group: 15 µL of 500 µg/mL miR-92a-3p overexpressed BM-MSC-Exos 3. OA group: 15 µL of PBS 4. Healthy control: 15 µL of PBS	Day 28 after collagenase induction	Not reported	Not reported	● Exo-miR-92a-3p group demonstrated significant reduced severity of cartilage matrix loss with higher Col II and aggrecan, and lower Wnt5a and MMP13 expressions in both gene and protein levels compared to the Exo and OA groups	Not reported
Wang et al^Citation79	SD rats Surgically induced OA	Intra-articular injection	1. Exo group: 100 µL of 1×10^11 particles/mL MSC-Exos 2. TGF-β1-Exo group: 100 µL of 1×10^11 particles/mL TGF-β1-MSC-Exos 3. TGF-β1-NC-Exo group: 100 µL of 1×10^11 particles/mL TGF-β1-MSC-NC-Exos 4. TGF-β1-miR135b inhibitor-Exo group: 100 µL of 1×10^11 particles/mL TGF-β1-MSC-miR135b inhibitor-Exos	Week 12 post-surgery	Not reported	Not reported	● Significant lower OARSI scores in the TGF-β1-Exo group than the Exo group, with high OARSI scores in the TGF-β1-miR135b inhibitor-Exo group ● TGF-β1-Exo group showed elevated number of chondrocytes, while dropped in chondrocyte number was recorded in the Exo and TGF-β1-miR135b inhibitor-Exo groups	Not reported
Zhang et al^Citation69	SD rats Surgically induced OCD	Multiple intra-articular injections immediately after surgery on weekly basis	1. Exo group: 100 µg/100 µL ESC-MSC-Exos 2. Contralateral control: 100 µL PBS	Week 2, 6 or 12	Not reported	Not reported	● Exo group demonstrated predominately hyaline cartilage regeneration (mostly Col II and very low Col I expression) and complete integration of neotissue with adjacent native cartilage with a smooth surface regularity and complete regeneration of subchondral bone at week 12 ● Wakitani scores of Exo group decreased from week 2 to 12 and the results were significantly lower than the contralateral control ● Enhanced proliferation, attenuated apoptosis, increased M2 macrophages and reduced M1 macrophages in both cartilage and synovium tissues, and decreased in M1-associated cytokines, ie, IL-1β and TNF-α, in synovial fluid of the Exo group	Not reported
Chen et al^Citation73	New Zealand white rabbits Surgically induced OCD	3D printed scaffold implantation	1. ECM/GelMA group: ECM/GelMA scaffold 2. GelMA group: GelMA scaffold 3. ECM/GelMA/Exo group: 3D printed ECM/GelMA/BM-MSC-Exo scaffold 4. OA group: untreated	Week 6 or 12 post-surgery	● ECM/GelMA/Exo group exhibited smooth and intact tissues and gave the highest ICRS macroscopic analysis scores	● MRI scanning demonstrated smooth neo-cartilage and great defect filling in both ECM/GelMA and ECM/GelMA/Exo groups ● µCT displayed increased ratio of bone volume to tissue volume, trabecular thickness and ossified tissues in the subchondral bone of both ECM/GelMA and ECM/GelMA/Exo groups	● ECM/GelMA and ECM/GelMA/Exo groups showed hyaline-like cartilage regeneration in the defect sites ● ECM/GelMA/Exo group has higher ICRS visual histological scores at week 12 ● Increased Col II and decreased of MMP13 expression in the synovial membrane of ECM/GelMA and ECM/GelMA/Exo groups ● ECM/GelMA/Exo group expressed the lowest MDA levels	No apparent pathological effects in myocardium, liver, and kidney 1 to 2 weeks after transplantation
Liu et al^Citation82	New Zealand white rabbits Surgically induced OA	Multiple intra-articular injections once a week	1. Exo group: 100 µg/mL PRP-Exos 2. PRP-As group: 100 µg/mL activated PRP 3. OA group: normal saline 4. Control: normal saline	Week 6 after surgery	Not reported	Not reported	● Exo group exhibited more regular arrangement of chondrocytes, clearer tidal line, reduced hyperplasia on articular cartilage surface and lower OARSI scores than the PRP-As and OA groups ● Exo group showed increased expression of Col II and RUNX2	No adverse events occurred
Wu et al^Citation64	C57BL/6 mice DMM induced OA	Multiple intra-articular injections twice a week, starting at week 4 after surgery	1. Exo group: 10 µL of 10^10 particles/mL IPFP-MSC-Exos 2. OA group: 10 µL PBS 3. Sham control: 10 µL PBS	Week 8 post-surgery	● Improved gait pattern (CatWalk gait analysis) after 6 weeks of exosome treatment	● Obvious green fluorescent dots (DiO-labeled IPFP-MSC-Exos) can be found at the defect sites	● Exo group showed integration of cartilage with smooth surface and lower OARSI scores confirming cartilage lesion was healed ● Exo group showed higher expression of Col II as well as lower expression of ADAMTS5 and MMP13	Not reported
		3 weeks of 10 µL antagomir pre-injection (once a week), starting at week 1 after surgery, followed by injection of Exos and antagomir twice a week for 4 weeks	1. PBS + antagomir-NC group: 10 µL PBS + antagomir-NC; 2. Exo + antagomir-NC group: 10 µL 10^10 particles/mL IPFP-MSC-Exos + antagomir-NC 3. Exo + antagomir-100-5p group: 10 µL 10^10 particles/mL IPFP-MSC-Exos + antagomir-100-5p	Week 8 post-surgery	Not reported	Not reported	● Exo + antagomir-100-5p group reversed the results of the Exo group	Not reported
Zhang et al^Citation70	SD rats MIA-induced TMJ-OA	Multiple intra-articular injections once a week, starting 2 weeks after OA induction	1. Exo group: 100 µg/50 µL of ESC-MSC-Exos 2. OA group: 50 µL of PBS 3. Sham control: needle pricks	Week 2, 4 or 8 post-treatment	● HWT improved gradually in the Exo group and reached the baseline level of the sham group at week 5	● µCT showed Exo group restored subchondral bone volume and architecture at week 8	● Exo group revealed significant reduced gene expressions of pro-inflammation (IL-1β), apoptosis (BAX), fibrosis (α-SMA) and pain (Substance P, CGRP, NGF, P75NTR and TrkA) and upregulated TIMP 2 and downregulated ADAMTS5 in condylar cartilage tissues ● Significant lower Mankin scores at week 4 and 8 in the Exo group ● Exo group showed smoother cartilage surface, improved cellularity, reduced fibrous cartilage thickening, minimal depletion of s-GAG in condylar cartilage lesion at week 4 and marked restoration of TMJ condylar structure at week 8 ● Exo group has lesser MMP13+ cells in condyle region at week 4; lesser IL-1β+ and iNOS+ cells, higher proliferative PCNA+ cells and lesser CCP3+ apoptotic cells at week 4 and 8	No adverse immune reactions observed
Zheng et al^Citation81	C57BL/6 mice Surgically induced OA	Multiple intra-articular injections once per week, starting 10 days after surgery	1. Exo group: 200 µg of primary chondrocyte-Exos 2. OA group: 20 µL saline 3. Sham control: Untreated	Week 4, 6 or 8 post-surgery	Not reported	● µCT demonstrated lower subchondral bone mineral density and smaller osteophyte formation at the joint margins in the Exo group	● Both femoral and tibia cartilage of the Exo group showed nearly complete preservation ● No obvious synovitis appearance in all groups ● Exo group expressed marked repression in MMP13 staining and elevated Col II staining in joint samples ● Significant lower OARSI scores in the Exo group ● Exo group exhibited higher level of M2 macrophages infiltration in the synovium and cartilage tissues	Not reported
Chen et al^Citation56	C57BL/6 mice Mechanical load induced OA	Single intra-articular injection immediately after mechanical induction	1. Exo group: 100 µL of 10^11 particles/mL BM-MSC-Exos 2. Exo-miR-136-5p group: 100 µL of 10^11 particles/mL miR-136-5p overexpressed BM-MSC-Exos 3. OA group: Untreated 4. Normal control: Untreated	One hour after injury	Not reported	Not reported	● Exo-miR-136-5p group showed lesser loss of cartilage matrix followed by the Exo and OA groups ● Exo-miR-136-5p group revealed higher level of Col II and aggrecan gene and protein expressions, decreased in ELF3 and MMP13 gene and protein expressions	Not reported
He et al^Citation75	SD rats MIA-induced OA	Multiple intra-articular injections once a week, starting one week after OA induction	1. Exo group: 40 µg/100 µL BM-MSC-Exos 2. OA group: 100 µL of normal saline 3. Sham control: 100 µL of normal saline	Week 6 post-treatment	● Joint injuries were alleviated in the Exo group ● Thermal PWL and mechanical PWT improved at weeks 2,4 and 6 in the Exo group	● In vivo imaging showed accumulation of PKH26 labeled BM-MSC-Exos in the joint cavity	● Articular cartilage of the Exo group regenerated, with small number of defects and fractures on cartilage surface ● Exo group has significantly reduced OARSI scores ● Exo group demonstrated notably increased in Col 2 protein expression level in chondrocytes and ECM, and decreased of MMP13 and Col 1 protein levels in cartilage tissue ● Exo group showed reduced expression of CGRP and iNOS in DRG ● Lower inflammatory cytokines (IL-1β, IL-6 and TNF-α) and higher anti-inflammatory cytokine (IL-10) in serum of Exo group	Not reported
Jin et al^Citation76	SD rats Surgically induced OA	Intra-articular injection, starting two weeks after OA induction	1. Exo group: BM-MSC-Exos 2. OA group: Normal saline	Week 7 post-treatment	Not reported	Not reported	● Lower observation and Mankin scores in the cartilage of the Exo group ● Notably decreased in inflammatory factors, AKP content and oxidative stress injury indicators, but increased in SOD in synovial fluid of the Exo group. ● Cartilage tissue of Exo group showed significant reduced MMP13, OCN and COMP gene and protein expressions	Not reported
			1. Exo group: BM-MSC-Exos 2. Exo-miR-9-5p group: miR-9-5p overexpressed BM-MSC-Exos 3.Exo-miR-9-5p inhibitor group: miR-9-5p inhibited BM-MSC-Exos 4.Exo-miR-mimic-NC group: miR-9-5p mimic NC BM-MSC-Exos 5. Exo-miR-inhibitor-NC group: miR-9-5p inhibitor NC BM-MSC-Exos 6. Liposomes miR-9-5p group: miR-9-5p-embedded liposomes 7. Sham control		Not reported	Not reported	● Exo-miR-9-5p group exhibited the lowest observation and Mankin scores among the treated groups ● Lower OA infiltration in the Exos, Exo-miR-mimic-NC and Exo-miR-inhibitor-NC group, and improved cartilage regeneration in the exo-miR-9-5p group ● Exo-miR-9-5p group has the lowest expression level of inflammatory factors, AKP content, and oxidative stress injury indicators, as well as highest level of SOD in synovial fluid among all the treated groups ● Exo-miR-9-5p group showed the lowest gene and protein expressions of MMP13, OCN and COMP in cartilage tissue compared to all the treated groups	Not reported
Jin et al^Citation57	Wistar rats Surgically induced OA	One-week intra-articular injection of treatments after surgery	1. Exo-miR-26a-5p group: 250 ng/5 µL of miR-26a-5p overexpressed BM-MSC-Exos 2. Exo-miR-NC group: 250 ng/5 µL of miR-NC BM-MSC-Exos 3. OA group: Untreated 4. Sham control: Untreated 5. Healthy control: Untreated	Week 8 post-surgery	Not reported	Not reported	● Exo-miR-26a-5p group has less pathological changes with the concomitant of reduced synovial tissue proliferation and suppressed inflammation ● Exo-miR-26a-5p group has lower MMP3 and MMP13 expression and higher apoptotic index in synovial cells ● Notably increased of miR-26a-5p expression and declined of PTGS2 expression in synovial tissue of the Exo-miR-26a-5p group ● Exo-miR-26a-5p group showed reduced serum IL-1β levels	Not reported
Liang et al^Citation77	SD rats DMM induced OA	Multiple intra-articular injections post-injury, once per week	1. Exo group: 100 µg of Exos particles in 100 µL PBS 2. Exo-miR140 group: 100 µg of Exo-miR140 particles in 100 µL PBS 3. CAP-Exo-miR140 group: 100 µg of CAP-Exo-miR140 particles in 100 µL PBS 4. OA group: Untreated 5. Sham control: Untreated	Week 8 post-surgery	Not reported	● Fluorescence microscopy showed that CAP-Exo-miR-140 mainly stayed in the articular cavity, while Exo-miR-140 distributed to other body parts and enriched in kidney	● CAP-Exo-miR140 group displayed smooth and flat cartilage surface, small joint space, proper cell alignment, normal subchondral bone and dense proteoglycan which was almost identical to the sham control and comparable OARSI scores with sham control ● CAP-Exo-miR140 group suppressed the MMP13 and Adamts5 protein levels in cartilage tissue ● Upregulation of miR-140 and downregulation of MMP13 gene expression in cartilage tissue in the CAP-Exo-miR140 group	Non-toxic to major organs (heart, liver, kidney, lung, and spleen)
Liu et al^Citation78	SD rats Surgically induced OCD	Intra-articular implantation	1. Exo group: Col-Tgel hydrogel with BM-MSC-Exos 2. KGN-Exo group: Col-Tgel hydrogel with KGN-BM-MSC-Exos 3. Gel group: Col-Tgel hydrogel 4. OA group: untreated 5. Normal control: untreated	Week 4, 6 and 8 post-surgery	● Better cartilage regeneration in the KGN-Exo group as indicated by smoother articular surface and better integration of newly formed cartilage with adjacent host cartilage ● KGN-Exo group exhibited higher ICRS macroscopic scores which were comparable with the normal group at 8 weeks	Not reported	● KGN-Exo group revealed better cartilage reconstruction with hyaline cartilage predominantly, corresponding to notable high ICRS visual histological scores ● KGN-Exo group showed increased s-GAG in cartilage tissue started at week 2 ● More lubricin and Col II positive cells and less Col I positive cells in KGN-Exo group compared to other groups except for the normal control group	Not reported
Qiu et al^Citation83	Mice Surgically induced OA	Not mentioned	1. Exo-Cur group: Curcumin pre-treated BM-MSC-Exos 2. Exo group: BM-MSC-Exos 3. OA group 4.Sham control	Not reported	Not reported	Not reported	● Exo-Cur group showed higher gene expression of miR-124 and miR-143 as well as lower protein expression of ROCK1, NF-kB and TLR9 that were similar to the sham control group ● Exo-Cur group has less apoptotic chondrocytes compared to the OA and Exo groups	Not reported
Wong et al^Citation63	New Zealand white rabbits Surgically induced OCD	Multiple intra-articular injections at day 0, day 7 and day 14 post-surgery	1. Exo + HA group: 1 mL of 3% (w/v) hyaluronic acid with 200 µg ESC-MSC-Exos 2. HA group: 1 mL of 3% (w/v) hyaluronic acid	Week 6 or 12 post-treatment	● Significant improvement in ICRS scores of Exo + HA group at week 6 and 12, associated with marked improvements of neotissue integration at the border zone ● Exo + HA group displayed improved mean Young’s moduli and stiffness of the repaired cartilage that approximated the normal tissue	Not reported	● Exo + HA group showed improvements in cartilage regeneration over time as confirmed by complete defect coverage by neotissue characterized by the presence of hyaline cartilage, normal cellularity and chondrocytic-like cells, high GAG and Col II deposition, and lower Col I deposition at week 12 ● Exo + HA group exhibited higher modified O’Driscoll scores than the HA group at week 6 and 12	No adverse events
Yan and Wu^Citation66	New Zealand rabbits Surgically induced cartilage defect	Multiple intra-articular injections on a weekly interval	1. 2D-Exo group: 500 µL of 1×10^10 particles/mL 2D cultured UC-MSC-Exos 2. 3D-Exo group: 500 µL of 1×10^10 particles/mL 3D cultured UC-MSC-Exos 3. OA group: 500 µL PBS	Week 4 post-treatment	● Significant improvement in ICRS macroscopic scores in the 3D-Exo group compared to the 2D-Exo and OA groups ● 3D-Exo group demonstrated more neotissue formation with smoother surface and better integration with the native hyaline cartilage at the surrounding	Not reported	● 3D-Exo group displayed partly hyaline cartilage and the defects showed greater surface regularity and better thickness of cartilage than the 2D-Exo group ● 3D-Exo group exhibited lower Wakitani score than the 2D-Exo and OA groups	Not reported
Zavatti et al^Citation67	CD rats MIA-induced OA	Intra-articular injection 3 weeks after OA induction (once for Cell and OA groups; twice for Exo group with 10 days interval)	1. Cell group: 50 µL of 5×10^5 AFSCs 2. Exo group: 50 µL of 100 µg AFSC-Exos 3. OA group: 50 µL of glucose/PBS 4.Contralateral control	Week 3 post-treatment	● Cell and Exo groups have higher pain tolerance, and the results were comparable to the normal control group	Not reported	● Exo group showed better cartilage regeneration as indicated by complete neotissue formation with good surface regularity compared to the cell-treated defects which exhibited few fissures on the cartilage surface ● Uniformed GAG distribution was demonstrated in the Exo group ● Both Exo and Cell groups exhibited improved OARSI scores ● Cell group displayed more intense Col II staining, whereas Exo group showed more regular distribution of Col II	No adverse inflammatory responses were observed
Zhang et al^Citation84	SD rats Surgically induced OA	Intra-articular injection every 3 days for 4 weeks, starting at week 4 post-operation	1. Exo group: 10 µL 10^10 particles/mL BM-MSC-Exos 2. OA group: 10 µL PBS 3. Sham control	Week 4 post-treatment	Not reported	● µCT showed less cartilage degradation, near-normal chondrocyte morphology and distribution, and less osteophyte formation around the joint treated with Exo ● Dil-labeled Exo were observed in the knee joint and taken up by the synovial cells	● Lower OARSI scores in the Exo group compared to the OA group ● Exo group demonstrated upregulated chondrogenic gene expressions and downregulated hypertrophic gene expressions ● Exo group has decreased synovial hyperplasia and cell filtration ● Exo group has less M1-positive cells and more M2-positive cells ● Exo group exhibited reduced pro-inflammatory cytokines (IL-1β, TNF-A) and increased anti-inflammatory cytokine (IL-10) in synovial fluid ● Exo group showed significant reduction in synovitis scores	Not reported
Zhou et al^Citation71	C57BL/6J mice Collagenase VII induced OA	Multiple intra-articular injections at day 7, 14 and 21 after collagenase induction	1. Exo group: BM-MSC-Exos 2. pExo group: polydactyly BM-MSC-Exos 3. OA group: Saline 4.Normal control	Day 28 post-collagenase VII injection	Not reported	Not reported	● pExo group alleviated cartilage damage evidenced by the significant lower OARSI scores than the OA and Exo groups	Not reported
Wang et al^Citation80	C57BL/6J mice Surgically induced OA	Single intra-articular injection at week 4 post-operation	1. Sham-Exo group: 200 µg sham-Exos 2. OA-Exo group: 200 µg OA-Exos 3. ATF4-OA-Exo group: 200 µg ATF4-OA-Exos 4. OA group 5.Sham control	Week 8 post-surgery	Not reported	● µCT showed reduced osteophyte formation in Sham-Exo and ATF4-OA-Exo groups, while OA-Exo group displayed enlarged osteophytes	● Sham-Exo and ATF4-OA-Exo groups alleviated pathological injury of articular tissues observed in the OA group, whereby the ATF4-OA-Exo group exerted greater therapeutic effect and lesser proteoglycan loss ● ATF4-OA-Exo group exhibited lower Mankin scores than the Sham-Exo group, while OA-Exo group aggravated the cartilage damage and exhibited the highest Mankin scores among all groups ● ATF4-OA-Exo group gave stronger effect in upregulating Col II levels and downregulating MMP13 levels ● ATF4-OA-Exo group was more potent in decreasing inflammatory cytokine levels in the cartilage ● ATF4-OA-Exo group partially restored the impeded autophagy of the OA cartilage	Not reported
Wang et al^Citation62	BALB/C mice 4°C water stimulated OA	Multiple intra-articular injection once a day, starting from day 20 after OA induction	1. Exo group: 30 µL of 10^11 particles/mL SM-MSC-Exos 2. Exo-155-5p group: 30 µL of 10^11 particles/mL miR-155-5p overexpressed SM -MSC-Exos 3. OA group: normal saline 4.Normal control	Two weeks post-treatment	Not reported	Not reported	● Exo-155-5p group revealed lower OARSI scores and higher chondrocyte number in femoral condyle ● Exo and Exo-155-5p groups reversed the increased caspase-3 and decreased Col II expressions in OA femoral condyle sections, but Exo-155-5p was more effective	Not reported
Yan et al^Citation65	SD rats Surgically induced cartilage defects	Multiple intra-articular injections on a weekly interval	1. S-Exo group: 100 µL of 1 mg/mL rotary cell culture system cultured UC-MSC-Exos 2. si-Exo group: 100 µL of 1 mg/mL rotary cell culture system cultured siRNA H19 transfected UC-MSC-Exos 3. OA group: 100 µL PBS	Week 4 or 8	● S-Exo group revealed reduced pain with higher LWT at week 3 ● Defects covered with neotissue at week 4 and were filled with uniform tissue and obscured boundaries at week 8 in the S-Exo group ● S-Exo group showed the highest ICRS scores	● Defects of S-Exo group displayed similar intensity to the adjacent cartilage through MRI at week 8 ● S-Exo group exhibited the lowest T2 values at week 4 and 8	● S-Exo group has the best surface regularity, highest glycosaminoglycan, most orderly tissues and best subchondral bone repair among the groups ● S-Exo group has significant lower Wakitani scores compared to the other groups ● S-Exo group displayed the highest matrix synthesis which consists mainly of Col II	Not reported

Abbreviations: µCT, micro computed tomography; ADAMTS, ADAM metallopeptidase with thrombospondin motifs; AFSC, amniotic fluid stem cell; AKP, alkaline phosphatase; BAX, Bcl-2 associated X-protein; BM-MSC, bone marrow-derived mesenchymal stem/stromal cell; CAP, chondrocyte-affinity peptide; CCP3, cleaved caspase-3; CGRP, calcitonin gene-related peptide; CLSM, confocal laser scanning microscopy; col I, type I collagen; col II, type II collagen; COMP, cartilage oligomeric matrix protein; DMM, destabilization of medial meniscus; DRG, dorsal root ganglion; ECM, extracellular matrix; EHG, exosome encapsulating hydrogel; ELF3, E74-like factor 3; ESC-MSC, embryonic stem cell-derived mesenchymal stem/stromal stem/stromal cell; Exo, exosome; GAG, glycosaminoglycan; GelMA, gelatin methacrylate; HWT, head withdrawal threshold; ICRS, International Cartilage Repair Society; IL, interleukin; iNOS, inducible nitric oxide synthase; IPFP-MSC, infrapatellar fat pad-derived mesenchymal stem/stromal cell; iPSC-MSC, induced pluripotent stem cell-derived mesenchymal stem/stromal cell; KGN, kartogenin; LWT, leg withdrawal threshold; MDA, malondialdehyde; MIA, monosodium iodoacetate; MMP, matrix metalloproteinase; MRI, magnetic resonance imaging; MSC, mesenchymal stem/stromal cell; NC, negative control; NGF, nerve growth factor; OA, osteoarthritis; OARSI, Osteoarthritis Research Society International; OCD, osteochondral defect; OCN, osteocalcin; OCT, optical coherence tomography; P75NTR, p75 neurotrophin receptor; PBS, phosphate-buffered saline; PCNA, proliferating cell nuclear antigen; PRP, platelet-rich plasma; PWL, paw withdrawal latency; PWT, paw withdrawal threshold; RUNX2, runt-related transcription factor 2; SD rat, Sprague Dawley rat; SMA, smooth muscle actin; SM-MSC, synovial membrane-derived mesenchymal stem/stromal cell; SOD, superoxide dismutase; TGF-β1, transforming growth factor beta 1; TIMP, tissue inhibitor of metalloproteinase; TMJ, temporomandibular joint; TNF-α, tumor necrosis factor-alpha; TrkA, tropomyosin receptor kinase A; UC-MSC, umbilical cord-derived mesenchymal stem/stromal cell.

Figure 2 Overview of the studies. The exosomes tested in the included studies were derived from human, murine, or rabbit amniotic fluid stem cells (AFSCs), embryonic stem cell-derived mesenchymal stem/stromal cells (ESC-MSCs), induced pluripotent stem cell-derived MSCs (iPSC-MSCs), bone marrow-derived MSCs (BM-MSCs), polydactyly BM-MSCs, synovial membrane-derived MSCs (SM-MSCs), infrapatellar fat pad-derived MSCs (IPFP-MSCs), umbilical cord-derived MSCs (UC-MSCs), chondrocytes, dendritic cells, platelet-rich plasma (PRP), and serum. The exosomes were administrated to the osteoarthritic joint through intra-articular injection or scaffold implantation. The exosomal bioactive compounds played an important role in cartilage and subchondral bone repair and regeneration. Overall, exosome therapy restored joint function, reduced joint pain, and improved the joint macroscopic, histological, and biochemical features.

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