Table 2.

The therapeutic outcome and pros/cons of exosome encapsulated traditional Chinese medicine (TCM) monomer in various neuronal disease model [[8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25]].

Naïve or modified exosome	TCM monomer	Animal/cell model	Administration way	Therapeutic outcome	Pros/cons	Refs.
Naïve exosomes	Ber/Pal	APP/PS1 mice	Intravenously: tail vein injection at the same time every two days for a total of 21 days	Anti-inflammatory effects both in vitro and in vivo; increasing drug accumulation in the hippocampus, cortex, and striatum; strengthening cognitive impairment and nerve injury in vivo by accelerating Aβ elimination and anti-inflammatory cytokine secretion	Pros: the Ber/Pal combined therapy exhibits better and more comprehensive therapeutic effects than single-drug treatment Cons: low yield of exosomes, lack of organic targeting	[8]
Naïve exosomes	Ber	SCI mice	Intravenously: tail vein injection	Anti-inflammatory and anti-apoptotic effect, alleviation moto function	Pros: exosome-Ber can cross BBB and blood spinal barrier, reach the spinal cord injury site through the cerebrospinal fluid circulation; exosomes provide a drug platform and have synergistic effect with drugs	[9]
Fe65-exosomes	Cory-B	5× FAD mice	Intraperitoneally or intravenously: alternate days for 45 days	Inducing neuronal cells autophagy and ameliorating cognitive function of AD mice	Prons: Fe65-exosomes can bypass BBB and target APP overexpressed neuronal cells	[10]
Naïve exosomes	Bai, Hed, and Nef	APP/PS1 mice	Intravenously: tail vein injection at a dose of 100 μg/kg	Reducing the level of huntingtin74, p301L tau, A53T α-synuclein, aggregation of Aβ (1−42), enhancing autophagy, and ameliorating the learning and memory ability in vivo	Pros: high bio-availability, crossing BBB with the molecular weight lower than 1109 Da of monomer Cons: off-target effects; not applicable to large-scale	[11]
Naïve exosomes	Bai	tMCAO and pMCAO rats	Intravenously: tail vein injection	Reducing cell apoptosis by attenuating ROS production in vitro and depressing the infarct area neurological scores while the integrity of neuronal structure in vivo	Pros: exosome-Bai easily cross the BBB, allowing more Bai to target brain tissues; the migratory and brain targeting abilities features of exosome-Bai was acquired from its origin cells (macrophages), to promote the accumulation of Bai in the brain ischemic region following pMCAO	[12]
Naïve exosomes	Cur	Injection of OA on one side of hippocampal area of mice	Intravenously: a single dose of cur at 0.4 mg/kg	Inhibiting tau phosphorylation through the Akt/GSK-3β pathway, ameliorating of learning and memory deficiencies in OA-induced AD mice	Pros: Cur-treated macrophage derived exosomes can enhance the penetration of cur across the BBB into the brain through interaction between LFA-1 and ICAM-1	[13]
Naïve exosomes	Cur	6-OHDA induced PD	Nasally: at a dose of 10 mg/kg body weight	Decreased the brain inflammation, aggregated of α-synuclein, and cell apoptosis in the dopaminergic TH positive neuron, and improved the impaired learning and memory ability in PD mice	Pros: hEnSCs-exosomes can delivery and transfer safe and effective payload in long-term, and sustain release manner into neuronal cells through intranasal injection way	[14]
PR-exosome	Cur	MPTP-induced PD model mice	Intranasally injection	Eliminating α-synuclein aggregation and promotion of the growth of neurite length and branches in vitro and the improvement of movement behavior and coordination ability in PD mice	Pros: three-Pronged Synergistic Treatment of PR-exosome/PP@Cur	[15]
Naïve exosomes	Cur	MOG peptide induced EAE mice	Intranasally: exosome-Cur was administered intranasally daily for 31 days using the protocol described above and was initiated on day 4 after immunization with the MOG peptide	Anti-inflammatory effects: reduction in the number of microglial cells	Pros: no side effects with nasally injection; exosomes are taken up by microglial cells (∼60%)/nonmicroglial cells (∼40%)	[16]
Naïve exosomes	Cur	MCAO rats	Intravenously: tail vein injection, exosomes-cur (10 μg/mL cur) was administered to MCAO rats after 2 h of occlusion	Decreasing of inflammatory cytokines expression level, ROS generation, Cyt c release, and infarct area; rescuing the loss of tight junction proteins and improving neurological performance in MCAO rats	Prons: exosomes protected Cur from degradation in plasma; accumulation of exosome-Cur in ischemic regions were driven by the inflammation-mediated targeting ability of exosomes	[17]
Naïve exosomes	Cur	Ischemia reperfusion-injured mic	Intranasally: alternate nostrils (2 μL × 5 times) started within an hour of I/R and sham surgery and continued till seven days.	Improvement in neurological scores, lessening in lesion volume, brain water content, and inflammation effect; normalization astrocytes and neuronal expression, decreasing in ICAM and improvement in VE-cadherin levels in brain vessels; and alleviating tight junction proteins loss	Pros: more solubility and stability of Cur in exosomes and the integrity of exosomes-Cur was preserved. Cons: the treatment of I/R-injured mice was started within an hour of injury which does not clinically implicate the conditions of the stroke patients who sometimes reach to the hospitals after hours of ischemic insult; the lack of additional mice groups treated with Cur and embryonic stem cells alone to compare the combined MESC-exosome-Cur effects; and time points analysis of available Cur concentrations in the blood and mice brain tissues	[18]
c(RGDyK)-exosomes	Cur	MACO mice	Intravenously: vein tail injection 12 h or 24 h after reperfusion	Decreasing pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) mediated by NF-κB and inhibiting expression level of caspase-3	Pros: the exosomes surface can be modified by bio-orthogonal chemistry easily and rapidly; cRGD-exosome can preserve intact exosomes shape and the bioactivity of their cargo, and can be internalized into brain cells to exert its neuroprotective roles Cons: whether the modified exosomes maintain the basic characteristics of natural exosomes like low immunogenicity should be evaluated in the future	[19]
RGE-exosomes	Cur	Orthotopic glioma-bearing nude mouse model	Intravenously: tail vein injection, every other day for total seven times	RGE-exosome-SPION/Cur had capability for targeted imaging of glioma and inhibiting the growth of tumor	Prons: the technology combination of exosome-SPION/Cur with MRI can early precise diagnosis and response evaluation of glioma Cons: the precise mechanism of exosome interaction with cells, exosome crossing BBB, the long-term effects of exosome, the optimal dose, treatment time, temperature control, and monitoring of magnetic flow hyperthermia for the synergistic effect of SPIONs need to be further explored	[20]
Naïve exosomes	ECG	Rotenone-induced SHSY5Y cells	–	Enhancing cell viability and antioxidative effects and inhibiting autophagy and cell apoptosis		[21]
Naïve exosomes	RSV	EAE mice	Intranasally: daily doses of RSV and exosome (3 mg/kg RSV, 30 μL)	Reducing of the expressions of pro-inflammatory cytokine (TGF-β, INF-γ, IL-6, and IL-17)	Pros: macrophages derived exosomes modified by click chemistry methods had little effect on the natural properties of exosomes, and fit for treatment of neurodegenerative diseases	[22]
mAb GAP43-exosomes	Que	MCAO/R model	Intravenously: tail vein injection	Inhibiting ROS production via activation of the Nrf2/HO-1 pathway in vitro and in vivo	Pros: the stability and solubility of exosomal Que were significantly enhanced; mAb GAP43 conjugated to the surface of exosomes can be internalized into I/R injury neuronal cells dependent on the interaction between exosome and GAP43 expressed on neurons in the ischemic region; and naïve plasma exosome exerted a synergistic neuroprotective effect against I/R injury	[23]
R-exosomes	TMZ/DHT	Tumor-bearing mice	Intravenously: tail vein every day, a total of six times.	R-exosome- TMZ/DHT could accurately target the tumor site and exerted good antitumor roles via activating immune system in vivo and in vitro, and reduction TMZ resistance in gliomas	Pros: R-exosome-TMZ/DHT have no toxicity or visible organ impairment in vivo	[24]
pHybrid-exosomes-Lips nanovesicles	SAB/CPT	orthotopic BALB/c nude mice bearing U87-Luc xenograft tumors	Intravenously: tail vein injection	The synergistic efficiency of pHybrid-SAB-CPT is major dependent on its cytotoxicity on cancer cells and anti-angiogenesis via depriving the nutrients supplied by new blood vessels in tumor, which are associated with SHP-2 upregulation induced STAT3 signal pathway suppression and anti-angiogenesis caused by VEGF inhibition	Prons: pHybrid/SAB-CPT can target tumor and accumulated in deep tumor regions and pHybrid nanovesicles have features in drug delivery, cell targeting, and tissue penetration	[25]

Ber: berberine; Pal: palmatine; APP: amyloid precursor protein; PS1: presenilin 1 ; SCI: spinal cord injury; BBB: blood-brain barrier; Cory-B: corynoxine-B; FAD: family Alzheimer's disease (AD); Bai: baicalin; Hed: hederagenin; Nef: neferine; tMCAO: transient middle cerebral artery occlusion; pMCAO: permanent middle cerebral artery occlusion/reperfusion; ROS: reactive oxygen species; Cur: curcumin; Akt: protein kinase B; GSK-3β: glycogen synthase kinase-3β; OA: okadaic acid; LFA-1: lymphocyte funciton-associated antigen 1; ICAM-1: endothelial intercellular adhesion molecule 1; 6-OHDA: 6-hydroxydopamine hydrochloride; PD: Parkinson's disease; TH: tyrosine hydroxylase; hEnSCs: human endometrial stem cells; PR: penetratin (P) and rabies virus glycoprotein (RVG29) peptides; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PP: ROS-responsive amphiphilic polymer poly(propylene sulfide)-polyethylene glycol (PPS-PEG); MOG: myelin oligodendrocyte glycoprotein; EAE: refractory experimental autoimmune encephalitis; I/R: ischemia and reperfusion injury; VE: vascular endothelial; MESC: mouse embryonic stem cell; c(RGDyK): cyclo(Arg-Gly-Asp-D-Tyr-Lys) peptide; TNF-α: Tumor necrosis factor-α; IL-1β: interleukin-1β; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; cRGD: cyclo(Arg-Gly-Asp); RGE: RGERPPR; SPION: superparamagnetic iron oxide nanoparticles; MRI: magnetic resonance imaging; ECG: epicatechin gallate; RSV: resveratrol; TGF-β: transforming growth factor-β; IFN-γ: interferon-γ; mAb: monoclonal antibody; GAP43: growth-associated protein-43; MCAO/R: middle cerebral artery occlusion/reperfusion ; Nrf2: nuclear factor erythroid-2-related factor 2; HO-1: heme oxygenase-1; R: reassembly; TMZ: temozolomide; DHT: dihydrotanshinone; pHybrid: BBB penetrated exosomes-liposome hybrid nanovesicles; Lips: lipidosomes; SAB: salvianolic acid B; CPT: cryptotanshinone; SHP-2: Src homology-2 domain-containing protein tyrosine phosphatase 2; STAT3: signal transducer and activator of transcription 3.