Table 4.

Summary of therapeutic efficacy and safety of MSC-secretome and EVs in preclinical animal models of PD.

Study	Animal model	Therapeutic agent	Route and dosage	Main outcomes
Yao et al. [101]	Male Sprague-Dawley rats treated with 6-OHDA	rBM-MSCs secretome + neural stem cells	Implantation of 50 mg of secretome + 5 × 103 cells	Generation of dopaminergic neurons; promotion of cell survival, migration, and integration into damaged brain areas.
				Amelioration of functional recovery, with significant reduction of apomorphine-induced rotational asymmetry and improved spatial learning ability.
Teixeira et al. [102]	Male Wistar Han rats (10 weeks) treated with 6-OHDA	Secretome from hBM-MSCs	Injection into the substantia nigra and striatum	Increase of dopaminergic neurons and neuronal terminals.
				Improvement of motor performance.
Chen et al. [103]	Adult male Sprague-Dawley rats treated with 6-OHDA	EVs from hUC-MSCs	Injection via tail vein of 200 μg of EVs	Reduction of dopaminergic neuron loss and apoptosis in the substantia nigra; upregulation of the dopamine level in the striatum.
				Relieved apomorphine-induced asymmetric rotation.
Teixeira et al. [104]	Male Wistar Han rats (9 weeks) treated with 6-OHDA	Secretome from hBM-MSCs vs levodopa	Injection into the substantia nigra and striatum	Increase of tyrosine hydroxylase-positive cell expression and terminals. Significant amelioration of the motor outcomes.
Mahendru et al. [105]	Male Sprague-Dawley rats treated with 6-OHDA	Secretome from rBM-MSCs	Intravenous injection of 25 μg of secretome per kg	Significant modulation of inflammatory, oxidative stress and apoptotic markers.
				Amelioration of impaired neurobehavioral parameters.
Xue et al. [106]	BALB/c mice (8–10 weeks) treated with MTPT	EVs from hA-MSCs	Intraperitoneal injection of 200 μm/mL of EVs	Promotion of angiogenesis in the striatum and substantia nigra.
				Increase in dopamine production.
Yang et al. [107]	Male transgenic mice expressing A53T human α-synuclein	EVs from hBM-MSCs delivering antisense oligonucleotides targeting α-synuclein	Stereotaxic injection into the right lateral ventricle of 24 μg of EVs containing 20 μg of antisense nucleotides	Decrease of α-synuclein expression.
				Decrease of dopaminergic neuron degeneration.
				Improvement of locomotor functions.
Cai et al. [109]	Male C57BL/6 mice (6 weeks) treated with MTPT	EVs form BM-MSCs	Injection via tail vein of 200 μL of EVs	Decrease of neuron loss and injury.
				Reduction of the inflammatory response by inhibiting Sp1 signaling.
Li et al. [108]	Sprague-Dawley rats treated with 6-OHDA	EVs from quiescent rBM-MSCs vs EVs from rBM-MSCs during dopaminergic differentiation	Stereotaxic injection into the striatum of 15 μg of EVs	Downregulation of IL-6, IL-1β and TNF-α.
				Reduction of the reactive oxygen species levels in the substantia nigra.
				Increased expression of tyrosine hydroxylase mRNA.
				Rescue of the rotation behavior and climbing speed.
				EVs from quiescent cells were more effective.
Ma et al. [110]	Mice treated with 6-OHDA	hUC-MSCs loaded with miR-181a–2–3p	Injection via tail vein of 200 μg of EVs	Reduction of dopamine neurons apoptosis.
				Reduction of oxidative stress.
Peng et al. [111]	Male C57BL/6 mice (6–8 weeks) treated with MTPT	EVs from mBM-MSCs + curcumin	Intranasal administration	Reduction of α-synuclein aggregates.
				Promotion of neuron function recovery.
				Alleviation of neuroinflammation.

6-OHDA = 6-hydro-xydopamine; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

r = rat; h = human; m = mouse.

BM = bone marrow; UC = umbilical cord; A = adipose.