Table 2.

Comparison between the cells and EVs regarding their intrinsic and application properties.

Properties		Cells	Extracellular vesicles
Intrinsic	Nature	- Natural, bilayer membranes with heterogeneous & cell-dependent distribution of glycolipids and glycoproteins	- Natural or synthetic, biomimetic (235), bilayer membranes
	Morphology	- Highly heterogeneous	- Heterogeneous
	Physicochemical	- Large	- Small, higher resistance to low temperatures (185)
	Prone to change	- Responsive to the environment (185, 186)	- Non-responsive to the environment (185)
	Proliferation	- Proliferative/self-replicative (185)	- Non-proliferative (185)
	Functional	- Self-renewal and differentiation capacity (in vitro) (236) - Secrete active compounds, can initiate tumorigenesis (237) - Senescence may induce thrombosis by obstruction of small blood vessels (237)	- Mediators of intercellular signaling/communication (238–240) - Paracrine and autocrine actions on stemness maintenance or cell differentiation (241) - Exhibit producer cell-dependent phenotypes (242–244) - EVs’ cargo can be drastically altered by culture conditions (243, 245) - EVs can mediate tumor initiation, progression, angiogenesis, and metastasis (235, 246) - EVs play role as disease biomarkers (239, 247, 248) - EVs demonstrate an age-related content (249) - MSC-EVs have prothrombotic effects (237)
Administration	Size	- Because of their size (10 µm), they can obstruct capillaries	- Pass through capillaries and BBB, and spinal cord barriers (250–253)
	Dosage	- Their potential for proliferation can limit the dose of administration	- They can have a wide range of administered doses
	Route	- Intravenous, intrathecal, intraventricular, subarachnoid, intra-arterial, intraperitoneal	- Intranasal, intravenous, intraperitoneal, intracranial, intracochlear, inhalation, oral, subcutaneous (141, 253–255)
In the body	Immunogenicity	- Low risk of immune rejection	- Lower risk of immune rejection (185, 187) - EVs are involved in antigen presentation (256) - Pathogenic EVs contain autoantigens (241) - Regulate the migration, proliferation, activation, and polarization of various immune cells (257, 258) - Promote a tolerogenic immune response (259, 260) - Inhibiting inflammatory response (259, 260) - Stimulate or suppress anti-cancer immunity
	Circulation time	- Short circulation life	- Longer circulation life (137, 261)
	Target cell selection	- Homing capability to some target sites, such as ischemic tissues	- Innate tropism to specific sites, which can also be engineered (76) - Exhibit cell-targeting properties (111)
	Long term effects	- Limited proliferation potential	- Not clear yet
	Tracking strategies	- X-ray–based methods (plain films and computed tomography (CT), optical imaging (bioluminescence and fluorescence), ultrasound/echocardiography, single-photon emission computed tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI) (262) - Single-cell Tracking of cells (175)	- Membrane labelling, vesicle interior labelling, labelling EV-specific cargoes (1, 69)
Manufacturing	Isolation	- Relatively simple isolation and characterization methods	- More complicated isolation steps (263)
	Storage	- Not possible to store them at room temperature, reduced viability after freeze and thaw	- Long-term preservation and storage stability (241)
	Off the shelf	- Not an off-the-shelf product	- Potent to be stored as lyophilized material (112) - Easier scale-up (185, 264, 265)
	Biopharmaceutical	- Biocompatible (137) - Biodistribution preference to lungs, liver, and kidneys (137) - Suitable for multi-drug delivery (137)	- Biocompatible (181) - Biodistribution preference to the liver, administration route-dependent biodistribution (266) - Untargeted accumulation in tumor tissues (137) - Intelligent Nano-carriers (267) - Multifunctional drug delivery systems (266)
Manipulation	Loading methods	- Various drug encapsulation methods (137, 268)	- Suitable manipulative platform (269) - Various exogenous and endogenous loading (205, 270) methods (235, 271, 272)
Regulations	Regulatory bodies and international communities	- FDA (Food and Drug Administration) - ISCT (International Society for Cell and Gene Therapy) - ISBT (International Society of Blood Transfusion) - ISSCR (International Society for Stem Cell Research)	- FDA (Food and Drug Administration) - ISCT (International Society for Cell and Gene Therapy) - ISEV (International Society for Extracellular Vesicles) - ISBT (International Society of Blood Transfusion)
	GMP standards and guidelines	- Well-defined GMP standards	- Lacking good manufacturing standards (137, 142) - Guidelines for novel EV-based therapeutics (111)