Nanotherapeutic and Stem Cell Therapeutic Strategies in Neurodegenerative Diseases: A Promising Therapeutic Approach

Figures & data

Figure 1 Advantages and limitations of various types of stem cells in the treatment of neurodegenerative diseases.

Figure 2 Various novel nanomaterials for the treatment of neurodegenerative diseases.

Figure 3 Schematic illustration of the cooperation of nanomaterials and stem cell therapies for brain repair in neurodegenerative diseases.

Abbreviations: BDNF, brain-derived neurotrophic factor; GDNF, glial cell line-derived neurotrophic factor; VEGF, vascular endothelial growth factor; IL-6, Interleukin-6; IL-10, Interleukin-10.

Table 1 A Summary of the Application of Nanomaterials and Stem Cells in Cooperation for the Treatment of Neurodegenerative Diseases

	Nanomaterials	Chemical Modifications/Loading Components/Additional Stimulation	Cell sources	In vitro/In vivo	Application	Ref.
Nanosupplements and nanocarrier	AuNPs	Electromagnetic stimulation	NSCs	In vivo	Increased hippocampal neurogenesis	[65]
	ssDNA-AuNPs	Circularly polarized light	NSCs	In vivo	Neuronal differentiation	[67]
	AuNPs GSH-cleavable nanocomplex	siRNA against SOX9	NSCs	In vitro	Stimulate and track NSC differentiation	[78]
	Dextran-coated iron oxide nanoparticles		hMSCs	In Vitro	DA-like neurons	[83]
	Magnetic Fe3O4 nanoparticles	Collagen	ESCs/iPSCs	In vivo	Promote migration and neuronal maturation	[64]
	Polymeric nanoparticles	RA	NSCs	In vitro	Neuronal differentiation	[77]
	PPFLMLLKGSTR peptide-amphiphilic solid lipid nanoparticles	NGF and RA	iPSCs	In Vitro	Neuronal differentiation	[73]
	Bioreducible Lipidoid Nanoparticles	Cas9 mRNA and sgRNA	hMSCs	In vitro	Neural-like differentiation	[72]
	Hydroxyapatite (HAp) nanorods		NSCs	In vitro/vivo	Neuronal differentiation	[54]
	RGD/TAT-functionalized Chitosan-graft-PEI-PEG nanovector	pCMV-EGFP-Ntf3	NSCs	In vitro	Neuronal differentiation	[74]
	TDNs	miR132-ASO	mESCs	In vitro	Enhance DAergic neurons differentiation	[79]
	Fullerene C60	Alanine	NSCs	In vitro	Proliferation and Neuronal Differentiation	[62]
	CNTs		NSCs	In vivo	Neuronal differentiation	[63]
	SeNPs		MSCs	In vivo	Neuroprotection	[70]
	Chitosan-coated SeNPs		MSCs	In vivo	Neuroprotection	[71]
	Chitosan-Gold Nanocomposites		MSCs	In vivo	Neuronal differentiation	[61]
	Metal-organic frameworks encapsulated nanozyme	siSOX9 and RA	mNSCs		Neuronal differentiation	[82]
2D and 3D nano-scaffolds	Graphene film	Electrical stimulation	MSCs	In vitro	Neuronal differentiation	[17]
	Gold nanocage-coated extracellular matrix surfaces	Laser irradiation	rNSCs	In vitro	Neuronal differentiation	[97]
	Graphene-coated homogeneous plasmonic metal (Au) nanoarrays	Dual-enhanced Raman scattering	hNSCs	In vitro	Neuronal differentiation	[87]
	Poly L-Lactic Acid Nanofibrous	Wireless electric stimulation	NSCs	In vitro	Neuronal differentiation	[89]
	Biocompatible silica nanozigzags	Sculptured by glancing angle deposition	NSCs	In vitro	Neuronal differentiation	[95]
	2D PCL nanofibrous scaffolds		NSCs	In Vitro	Neuronal cells and glial cells	[88]
	GO-coated electrospun nanofibrous scaffolds	Methylene blue (MB)	NPCs	In vitro	Neuroprotection	[99]
	Silk fibroin nanofibrous scaffolds	MicroRNA-222- chitosan nanoparticles	NSCs	In vitro	Neuronal differentiation	[98]
	Ordered nanopatterned topography PLCL scaffolds	GO functionalization	NSCs	In vitro	Neurons and glial cells	[25]
	AuNPs-contained PCL and chitosan scaffolds		MSCs	In vitro	Neuronal differentiation	[91]
	Electrospun PCL and graphene nanocomposite		MSCs	In Vitro	Functional dopaminergic neurons	[90]
	3D PLGA microfiber scaffolds		iPSC	In vitro	Neuronal differentiation	[102]
	3D alginate hydrogel	MMP and RGD peptides	NSCs	In vivo	Dopamine neurons	[22]
	3D rGO-collagen hybrid scaffold		MSCs	In vitro	Neuronal differentiation	[107]
	3D hydroxyethyl cellulose/glycine/RuO2 composite scaffolds		MSCs	In vitro	Neuronal differentiation	[101]
	3D-MnO2-laminin hybrid nanoscaffolds	DAPT drugs	hiPSC-NSCs	In vivo	Neuronal differentiation	[13]
	Chromatin-inspired supramolecular nanofibers	K6-PEG-RGD peptide	NSCs	In situ	Oligodendrocytes	[100]
Nanotechnology-based stem cell labeling and tracking	Magnetic silica core-shell nanoparticle	MRI	MSCs	In vivo	Labeling and delivery of transplanted MSCs	[116]
	AuNP-PLL-RITC Nanocomplexes	Micro-CT.	MSCs	In vivo	Labeling and tracking	[121]
	AuNPs as labeling agents	X-ray CT	MSCs	In vivo	Tracking migration and homing of MSCs-derived exosomes	[123]
	SPIONs	MRI	hESCs	In vivo	Ameliorate motor function and cell tracking	[117]
	PLL hydrobromide -SPIONs	MRI	MSCs	In vivo	Labeling and delivery of MSCs	[84]
	SPIONs	MRI	MSCs	In vivo	Labeling and delivery of MSCs	[118]
	Magnetic Fe3O4 and polydopamine shells	MRI	MSCs	In vivo	Labeling and delivery of MSCs	[119]
	Hydrophobic SPIONs-negative let-7b ASO	MRI	NSCs	In vivo	Tracing transplanted cells/secretion of BDNF	[120]
	TPETPAFN dots		hESCs	In vivo	Labeling of transplanted ESCs	[126]
	PBAE-PLGA-Ag2S-RA-siSOX9 nanoformulation		NSCs	In vivo	Aβ clearance and Neural differentiation	[127]

Figure 4 Schematic representation of the application of nanomaterials in stem cell therapy of neurodegenerative diseases.

Chang Y, Cho B, Lee E, et al. Electromagnetized gold nanoparticles improve neurogenesis and cognition in the aged brain. Biomaterials. 2021;278:121157. doi:10.1016/j.biomaterials.2021.121157

 PubMed Web of Science ®Google Scholar

Qu A, Sun M, Kim JY, et al. Stimulation of neural stem cell differentiation by circularly polarized light transduced by chiral nanoassemblies. Nat Biomed Eng. 2021;5(1):103–113. doi:10.1038/s41551-020-00634-4

 PubMed Web of Science ®Google Scholar

Zhang R, Wang Z, Yang Z, et al. RNA-silencing nanoprobes for effective activation and dynamic imaging of neural stem cell differentiation. Theranostics. 2019;9(18):5386–5395. doi:10.7150/thno.35032

 PubMed Web of Science ®Google Scholar

Chung TH, Hsu SC, Wu SH, et al. Dextran-coated iron oxide nanoparticle-improved therapeutic effects of human mesenchymal stem cells in a mouse model of Parkinson’s disease. Nanoscale. 2018;10(6):2998–3007. doi:10.1039/C7NR06976F

 PubMed Web of Science ®Google Scholar

Semeano AT, Tofoli FA, Correa-Velloso JC, et al. Effects of magnetite nanoparticles and static magnetic field on neural differentiation of pluripotent stem cells. Stem Cell Rev Rep. 2022;18(4):1337–1354. doi:10.1007/s12015-022-10332-0

 PubMed Web of Science ®Google Scholar

Ferreira R, Fonseca MC, Santos T, et al. Retinoic acid-loaded polymeric nanoparticles enhance vascular regulation of neural stem cell survival and differentiation after ischaemia. Nanoscale. 2016;8(15):8126–8137. doi:10.1039/C5NR09077F

 PubMed Web of Science ®Google Scholar

Kuo YC, Shih-Huang CY, Rajesh R. Enhanced integrin affinity and neural differentiation of induced pluripotent stem cells using Ln5-P4-grafted amphiphilic solid lipid nanoparticles. Mater Sci Eng C Mater Biol Appl. 2021;118:111339. doi:10.1016/j.msec.2020.111339

 PubMed Web of Science ®Google Scholar

Zhao X, Glass Z, Chen J, Yang L, Kaplan DL, Xu Q. mRNA delivery using bioreducible lipidoid nanoparticles facilitates neural differentiation of human mesenchymal stem cells. Adv Healthc Mater. 2021;10(4):e2000938. doi:10.1002/adhm.202000938

 PubMed Web of Science ®Google Scholar

Hao M, Zhang Z, Liu C, et al. Hydroxyapatite nanorods function as safe and effective growth factors regulating neural differentiation and neuron development. Adv Mater. 2021;33(33):e2100895. doi:10.1002/adma.202100895

 PubMed Web of Science ®Google Scholar

Wu D, Zhang Y, Xu X, et al. RGD/TAT-functionalized chitosan-graft-PEI-PEG gene nanovector for sustained delivery of NT-3 for potential application in neural regeneration. Acta Biomater. 2018;72:266–277. doi:10.1016/j.actbio.2018.03.030

 PubMed Web of Science ®Google Scholar

Wei M, Li S, Yang Z, Cheng C, Li T, Le W. Tetrahedral DNA nanostructures functionalized by multivalent microRNA132 antisense oligonucleotides promote the differentiation of mouse embryonic stem cells into dopaminergic neurons. Nanomedicine. 2021;34:102375. doi:10.1016/j.nano.2021.102375

 PubMed Web of Science ®Google Scholar

Ren H, Li J, Peng A, et al. Water-soluble, alanine-modified fullerene C60 promotes the proliferation and neuronal differentiation of neural stem cells. Int J Mol Sci. 2022;23(10):5714. doi:10.3390/ijms23105714

 PubMed Web of Science ®Google Scholar

Marei HE, Elnegiry AA, Zaghloul A, et al. Nanotubes impregnated human olfactory bulb neural stem cells promote neuronal differentiation in Trimethyltin-induced neurodegeneration rat model. J Cell Physiol. 2017;232(12):3586–3597. doi:10.1002/jcp.25826

 PubMed Web of Science ®Google Scholar

Gholamigeravand B, Shahidi S, Afshar S, et al. Synergistic effects of adipose-derived mesenchymal stem cells and selenium nanoparticles on streptozotocin-induced memory impairment in the rat. Life Sci. 2021;272:119246. doi:10.1016/j.lfs.2021.119246

 PubMed Web of Science ®Google Scholar

Soleimani Asl S, Amiri I, Samzadeh-Kermani A, Abbasalipourkabir R, Gholamigeravand B, Shahidi S. Chitosan-coated Selenium nanoparticles enhance the efficiency of stem cells in the neuroprotection of streptozotocin-induced neurotoxicity in male rats. Int J Biochem Cell Biol. 2021;141:106089. doi:10.1016/j.biocel.2021.106089

 PubMed Web of Science ®Google Scholar

Hung HS, Yang YC, Chang CH, et al. Neural differentiation potential of mesenchymal stem cells enhanced by biocompatible chitosan-gold nanocomposites. Cells. 2022;11(12):1861. doi:10.3390/cells11121861

 PubMed Web of Science ®Google Scholar

Yu D, Ma M, Liu Z, et al. MOF-encapsulated nanozyme enhanced siRNA combo: control neural stem cell differentiation and ameliorate cognitive impairments in Alzheimer’s disease model. Biomaterials. 2020;255:120160. doi:10.1016/j.biomaterials.2020.120160

 PubMed Web of Science ®Google Scholar

Guo Z, Sun C, Yang H, et al. Regulation of neural differentiation of ADMSCs using graphene-mediated wireless-localized electrical signals driven by electromagnetic induction. Adv Sci. 2022;9(14):e2104424. doi:10.1002/advs.202104424

 Web of Science ®Google Scholar

Jung S, Harris N, Niyonshuti II, et al. Photothermal response induced by nanocage-coated artificial extracellular matrix promotes neural stem cell differentiation. Nanomaterials. 2021;11(5):1216. doi:10.3390/nano11051216

 Web of Science ®Google Scholar

Yang L, Lee JH, Rathnam C, Hou Y, Choi JW, Lee KB. Dual-enhanced raman scattering-based characterization of stem cell differentiation using graphene-plasmonic hybrid nanoarray. Nano Lett. 2019;19(11):8138–8148. doi:10.1021/acs.nanolett.9b03402

 PubMed Web of Science ®Google Scholar

Lu X, Sun C, Chen L, et al. Stemness maintenance and massproduction of neural stem cells on Poly L-Lactic acid nanofibrous membrane based on piezoelectriceffect. Small. 2022;18(13):e2107236. doi:10.1002/smll.202107236

 PubMed Web of Science ®Google Scholar

Zhang S, Sun P, Lin K, et al. Extracellular nanomatrix-induced self-organization of neural stem cells into miniature substantia nigra-like structures with therapeutic effects on parkinsonian rats. Adv Sci. 2019;6(24):1901822. doi:10.1002/advs.201901822

 Web of Science ®Google Scholar

Asheghali D, Lee SJ, Furchner A, et al. Enhanced neuronal differentiation of neural stem cells with mechanically enhanced touch-spun nanofibrous scaffolds. Nanomedicine. 2020;24:102152. doi:10.1016/j.nano.2020.102152

 PubMed Web of Science ®Google Scholar

Wang L, Liu X, Fu J, et al. Release of methylene blue from graphene oxide-coated electrospun nanofibrous scaffolds to modulate functions of neural progenitor cells. Acta Biomater. 2019;88:346–356. doi:10.1016/j.actbio.2019.02.036

 PubMed Web of Science ®Google Scholar

Li Z, Meng Z, Zhao Z. Silk fibroin nanofibrous scaffolds incorporated with microRNA-222 loaded chitosan nanoparticles for enhanced neuronal differentiation of neural stem cells. Carbohydr Polym. 2022;277:118791. doi:10.1016/j.carbpol.2021.118791

 PubMed Web of Science ®Google Scholar

Polo Y, Luzuriaga J, Iturri J, et al. Nanostructured scaffolds based on bioresorbable polymers and graphene oxide induce the aligned migration and accelerate the neuronal differentiation of neural stem cells. Nanomedicine. 2021;31:102314. doi:10.1016/j.nano.2020.102314

 PubMed Web of Science ®Google Scholar

Rahimzadegan M, Mohammadi Q, Shafieian M, Sabzevari O, Hassannejad Z. Influence of reducing agents on in situ synthesis of gold nanoparticles and scaffold conductivity with emphasis on neural differentiation. Mater Sci Eng C Mater Biol Appl. 2021;134:112634.

 Google Scholar

Rawat S, Jain KG, Gupta D, et al. Graphene nanofiber composites for enhanced neuronal differentiation of human mesenchymal stem cells. Nanomedicine. 2021;16(22):1963–1982. doi:10.2217/nnm-2021-0121

 PubMed Web of Science ®Google Scholar

Ranjan VD, Qiu L, Lee JW, et al. A microfiber scaffold-based 3D in vitro human neuronal culture model of Alzheimer’s disease. Biomater Sci. 2020;8(17):4861–4874. doi:10.1039/D0BM00833H

 PubMed Web of Science ®Google Scholar

Qiao S, Liu Y, Han F, et al. An intelligent neural stem cell delivery system for neurodegenerative diseases treatment. Adv Healthc Mater. 2018;7(12):e1800080. doi:10.1002/adhm.201800080

 PubMed Web of Science ®Google Scholar

Guo W, Wang S, Yu X, et al. Construction of a 3D rGO-collagen hybrid scaffold for enhancement of the neural differentiation of mesenchymal stem cells. Nanoscale. 2016;8(4):1897–1904. doi:10.1039/C5NR06602F

 PubMed Web of Science ®Google Scholar

Mabrouk M, Ismail E, Beherei H, et al. Biocompatibility of hydroxyethyl cellulose/glycine/RuO2 composite scaffolds for neural-like cells. Int J Biol Macromol. 2022;209(Pt B):2097–2108. doi:10.1016/j.ijbiomac.2022.04.190

 PubMedGoogle Scholar

Yang L, Chueng SD, Li Y, et al. A biodegradable hybrid inorganic nanoscaffold for advanced stem cell therapy. Nat Commun. 2018;9(1):3147. doi:10.1038/s41467-018-05599-2

 PubMedGoogle Scholar

Zhao H, Xu J, Peng K, et al. Supramolecular nanofibers for encapsulation and in situ differentiation of neural stem cells. Adv Healthc Mater. 2020;9(1):e1901295. doi:10.1002/adhm.201901295

 PubMed Web of Science ®Google Scholar

Kim KY, Chang KA. Therapeutic potential of magnetic nanoparticle-based human adipose-derived stem cells in a mouse model of Parkinson’s disease. Int J Mol Sci. 2021;22(2):654.

 PubMed Web of Science ®Google Scholar

Kim T, Lee N, Arifin DR, et al. In vivo Micro-CT imaging of human mesenchymal stem cells labeled with Gold-Poly-L-Lysine nanocomplexes. Adv Funct Mater. 2017;27(3). doi:10.1002/adfm.201604213

 Web of Science ®Google Scholar

Perets N, Betzer O, Shapira R, et al. Golden exosomes selectively target brain pathologies in neurodegenerative and neurodevelopmental disorders. Nano Lett. 2019;19(6):3422–3431. doi:10.1021/acs.nanolett.8b04148

 PubMed Web of Science ®Google Scholar

Islam J, So KH, Kc E, et al. Transplantation of human embryonic stem cells alleviates motor dysfunction in AAV2-Htt171-82Q transfected rat model of Huntington’s disease. Stem Cell Res Ther. 2021;12(1):585. doi:10.1186/s13287-021-02653-7

 PubMed Web of Science ®Google Scholar

Moayeri A, Darvishi M, Amraei M. Homing of Super Paramagnetic Iron Oxide Nanoparticles (SPIONs) labeled adipose-derived stem cells by magnetic attraction in a rat model of Parkinson’s disease. Int J Nanomed. 2020;15:1297–1308. doi:10.2147/IJN.S238266

 PubMed Web of Science ®Google Scholar

Hour FQ, Moghadam AJ, Shakeri-Zadeh A, Bakhtiyari M, Shabani R, Mehdizadeh M. Magnetic targeted delivery of the SPIONs-labeled mesenchymal stem cells derived from human Wharton’s jelly in Alzheimer’s rat models. J Control Release. 2020;321:430–441. doi:10.1016/j.jconrel.2020.02.035

 PubMed Web of Science ®Google Scholar

Wang Y, Jiang J, Fu X, et al. Fe3O4@polydopamine nanoparticle-loaded human umbilical cord mesenchymal stem cells improve the cognitive function in Alzheimer’s disease mice by promoting hippocampal neurogenesis. Nanomedicine. 2022;40:102507. doi:10.1016/j.nano.2021.102507

 PubMed Web of Science ®Google Scholar

Li Y, Li Y, Ji W, et al. Positively charged polyprodrug amphiphiles with enhanced drug loading and reactive oxygen species-responsive release ability for traceable synergistic therapy. J Am Chem Soc. 2018;140(11):4164–4171. doi:10.1021/jacs.8b01641

 PubMed Web of Science ®Google Scholar

Jang SE, Qiu L, Cai X, et al. Aggregation-induced emission (AIE) nanoparticles labeled human embryonic stem cells (hESCs)-derived neurons for transplantation. Biomaterials. 2021;271:120747. doi:10.1016/j.biomaterials.2021.120747

 PubMed Web of Science ®Google Scholar

Huang D, Cao Y, Yang X, et al. A nanoformulation-mediated multifunctional stem cell therapy with improved beta-amyloid clearance and neural regeneration for Alzheimer’s disease. Adv Mater. 2021;33(13):e2006357. doi:10.1002/adma.202006357

 PubMed Web of Science ®Google Scholar