Table 5.

Different strategies to modify EVs for OA therapy.

Strategies		Methods	Advantages	Disadvantages	Examples	Ref.
Modifying donor cells	Biochemical factors	Co-incubation	Simple;	Cytotoxicity;	Delivery of Curcumin	[220]
			No significant impact on EV structures;	Susceptible loading efficiency;
		Transfection	High specificity;	Induce donor cell apoptosis;	Overexpression of miR-140	[221]
			No significant impact on EVs structures;	Low loading efficiency;
		Hypoxia	Maintain stemness;	Complex; Low specificity; Affect donor cell proliferation;	Hypo-sEVs had high expression of miR-216a	[222]
			Influence the differentiation of stem cells;
	Mechanical factors	Mechanical stress	Simulated internal environment; No damage to membrane integrity;	Complex;	Stimulated by LIPUS	[223]
				Low specificity;
		3D culture	Mass production;	Complex;	Cultured in hollow-fiber bioreactor	[224]
			Increase the cargoes and ability of EVs;	Low specificity;
Modifying EVs directly	Loading cargoes	Direct mixing	Simple and quick;	Only suitable for hydrophobic compounds;	Delivery of COS	[225]
		electroporation	Simple and quick;	Affect integrity;	Delivery of KGN	[30]
			High efficiency;	Not suitable for RNAs with special structures;
	Modifying membrane	Fusion with proteins	Improve the targeting;	Affect the functions of cargoes;	Fused with MSCs binding peptide E7	[30,31]
		Reverse surface charge	Improved distribution, retention ability and bioavailability;	Affects integrity and cargoes;	Modified with PPD	[32]
				Low homogeneity;
	Generating biomimetic EV	Hybrid EVs	High load capacity; Controllable production process; Scalability	Increase the difficulty of preparation;	Fused with liposomes to carry Cas9 sgMMP-13	[31]
				Low homogeneity