TABLE 2.

Modification strategies for EV engineering.

Modification methods		Approaches	Results	References
Indirect MSC modification strategies	Manipulating gene transfection	Virus transfection	Overexpressing miR-140–5p, and alleviating OA progress through downregulating VEGFA	Liu et al. (2022)
		Plasmid transfection	Upregulating circRNA_0001236, and inhibiting cartilage degradation via miR-3677–3p/Sox9	Mao et al. (2021)
		Plasmid transfection	Overexpressing lncRNA H19, and promoting chondrogenesis through miR-29b-3p/FOXO3	Yan et al. (2021)
	Co-incubating donor cells with bioactive molecules	Co-incubation with curcumin	Reducing the oxidative stress and protecting chondrocytes	Xu et al. (2022)
		Co-incubation with TGF-β1	Enhancing the M2 polarization via miR-135b/MAPK6 axis	Wang and Xu, (2021)
		Co-incubation with IL-1β	Inhibiting inflammation of OA	Kim et al. (2021)
		Co-incubation with LPS	Inhibiting cartilage matrix degradation	Duan et al. (2021)
	Engineering cell culture micro-environment	3D culture	Promoting chondrogenesis	Yan and Wu, (2020)
		Dynamic mechanical stimulation	Inhibiting inflammation via NF-κB signal pathway	Liao et al. (2021)
		Hypoxia micro-environment culture	Enhancing cartilage repair	Rong et al. (2021)
Direct EV modification strategies	Enriching EV cargos	Direct mixture method	Loading COS into EVs, and promoting anabolic related genes expression of chondrocytes	Li et al. (2021a)
		Electroporation	Loading KGN into EVs, and improving cartilage repair	Xu et al. (2021)
	Modifying EV membrane	E7 peptide modifying EV surface	Targeting synovial fluid-derived MSCs	Xu et al. (2021)
		Fusing CAP with EV surface protein	Improving the chondrocyte target ability	Liang et al. (2020)
		Modifying EVs with PPD	Regulating EV surface charge potential, and promoting EV penetration into cartilage matrix	Feng et al. (2021)