Table 2.

Summary of modRNA-induced transdifferentiation used in therapeutic investigations.

Cell Sources	modRNA	Modifications	Transfection Methods	Transfection Numbers	Total modRNA	Differentiated Cell Types	Animal Models	Therapeutic Effects	References
modRNA-induced hiPSCs	MYOD	5mC, ψU, 5′ UTR containing Kozak sequence, α-Globin 3′ UTR, Poly-A tail, ARCA	RNAiMAX	3	3.6 μg	Myogenic cells	N/A	N/A	[47]
Human foreskin fibroblasts	MYOD	5mC, ψU, 5′ UTR containing Kozak sequence, 3′ UTR, Poly-A tail, ARCA	Stemfect RNA transfection reagent	4	1.2 μg	Myoblasts	N/A	MYOD1 modRNA can directly transdifferentiate human fibroblasts into myoblasts without a transgene footprint	[66]
Mouse fibroblasts and hMSCs	MYOD	5mC, ψU, ARCA	Lipofectamine 2000	3	0.75 μg	Skeletal myoblasts	N/A	Defining optimized properties of modRNA-based protein expression in adult stem cells and fibroblasts	[110]
hESC-derived ISL1+ heart progenitors	VEGF-A	5mC, ψU, 5′ UTR containing Kozak sequence, α-Globin 3′ UTR, Poly-A tail, ARCA	RNAiMAX	In vitro-2 In vivo-1	In vitro-2 μg In vivo-5 μg	Human Isl1+ vascular endothelial cells	N/A	VEGF-A modRNA promotes not only the endothelial specification but also engraftment, proliferation, and survival (reduced apoptosis) of the human Isl1+ progenitors in vivo	[90]
Heart WT1+ epicardial progenitors	VEGF-A	5mC, ψU, 5′ UTR containing Kozak sequence, α-Globin 3′ UTR, Poly-A tail, ARCA	RNAiMAX	In vitro-1 In vivo-1	In vitro-3 μg In vivo-100 μg/heart	Endothelial cells and cardiovascular cells	Mouse myocardial infarction model	Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction	[102]
Endogenous heart epicardial progenitors	IGF1	5mC, ψU, ARCA	N/A	1	100 μg/heart	Epicardial adipose tissues	Mouse myocardial injury	An IGF1R modRNA-induced pathway drives epicardial adipose tissue formation after myocardial injury	[103]
Human ADSCs	Brachyury	5mC, Poly-A tail, ARCA	Microencapsulated-modified-mRNA (M3RNA) technique	1	1.75 μg	Cardiopoietic stem cells	Mouse myocardial infarction	Intramyocardial delivery of Brachyury modRNA-induced cardiopoietic stem cells can improve cardiac performance and protect against decompensated heart failure	[104]
Cardiac fibroblasts	Gata4, Mef2c, Tbx5	5mC, ψU, Poly-A tail, ARCA	C-Lipo (polyarginine-fused heart-targeting peptide and lipofectamine complex)	14	16.8 μg	Cardiomyocytes	N/A	C-Lipo can enhance modRNA transfection and results in the direct reprogramming of fibroblasts into cardiomyocytes	[111]
hESCs	ETV2, GATA2	5mC, ψU, Poly-A tail, ARCA	Electroporation	2	7 μg	CD43+ hematopoietic cells	N/A	Transient expression of ETV2 and GATA2 is indeed sufficient to commit the hPSCs to blood fate	[91]
Human skin fibroblasts	ETV2	Poly-A tail, Cap	Electroporation	1	3 μg	Endothelial progenitor cells	Hindlimb ischemia model	ETV2 modRNA combined with hypoxia can produce functional EPCs from fibroblasts and improve mouse ischemia	[114]
Human iPSCs	ETV2	ψU, Poly-A tail, ARCA	TransIT-mRNA	1	0.2 μg	Hemogenic endothelium	N/A	ETV2 modRNA-induced hematoendothelial progenitors can differentiate into functional neutrophils in the presence of G-CSF and Am580	[93,94]
Human iPSCs	ETV2	5′ UTR, 3′ UTR, Poly-A tail, Cap	Electroporation or RNAiMax	1	0.6 μg	Endothelial cells	N/A	Direct differentiation of human iPSCs into endothelial cells via transient modulation of ETV2 modRNA	[92]
hESCs	PDX1	5mC, ψU, Poly-A tail, ARCA	Electroporation	1	N/A	Insulin-producing cells	N/A	PDX1 modRNA can directly induce the transdifferentiation of insulin-producing cells	[95]
Mouse pancreas-derived MSCs	PDX1	5mC, ψU, Poly-A tail, ARCA	TransIT-mRNA	1	N/A	Insulin-producing cells	N/A	Mouse pMSCs can be transdifferentiated into functional glucose-responsive insulin-producing cells through transfecting PDX-1 modRNA	[96]
Pancreatic exocrine cells AR42J	PDX1, Ngn3, MafA	5mC, ψU, Poly-A tail, ARCA	Lipofectamine MessengerMAX	10	15 μg	Insulin-producing cells	N/A	Reprogramming of pancreatic exocrine cells into insulin-producing cells through modRNAs, represents a promising approach for cell-based diabetes therapy	[112]
Human pancreatic duct-derived cells	MafA	5mC, ψU, 5′ UTR containing Kozak sequence, α-Globin 3′ UTR, Poly-A tail, ARCA	jetPEI	7	8.4 μg	Insulin-producing cells	Diabetic SCID-beige mice	MafA modRNA can drive the reprogramming of human pancreatic duct-derived cells into functional insulin-secreting cells, and reverse diabetes	[115]
Human pluripotent stem cells	NEUROG1, NEUROG2, NEUROG3, NEUROD1, and NEUROD2	5mC, ψU, 5′ UTR, 3′ UTR, Poly-A tail, ARCA	Lipofectamine MessengerMAX	2	2 μg	Neurons	N/A	The modRNA cocktail can differentiate hPSCs into motor neurons	[97]
Human adult fibroblasts	SOX2, PAX6	5′ UTR, 3′ UTR, Poly-A tail, Cap	Lipofectamine RNAiMAX	4	8 μg	Neural precursor cells	N/A	Direct conversion of human fibroblasts into neural precursor cells using modRNA	[113]
HumanBMSCs	BMP-2	5mC, ψU, Poly-A tail, ARCA	Branched PEI	1	25 μg	Bone regeneration	Rat calvarial bone defect model	Scaffolds loaded with BMP-2 modRNA can enhance bone regeneration	[106]
Rat mesenchymal stem cells	BMP-2	5mC, 2TU, Poly-A tail, ARCA	C12-EPE	1	2.5 μg	Bone regeneration	Rat femur defect model	Delivering hBMP-2 modRNA to a femur defect can result in new bone tissue formation	[107]
Rat mesenchymal stem cells	BMP-2	5mC, 2TU, Poly-A tail, Cap	Proprietary lipid	1	2.5 μg	Bone regeneration	Rat femur defect model	BMP-2 modRNA-loaded collagen sponges can induce bone regeneration	[108]
HumanBMSCs	BMP-9, BMP-2	5mC, ψU, Poly-A tail, ARCA	PEI	1	50 μg	Bone regeneration	Rat calvarial bone defect model	BMP-9 modRNA can induce increased connectivity density of the regenerated bone compared with BMP-2 modRNA	[109]
Rat BMSCs	BMP-2	5mC, 2TU, Poly-A tail, ARCA	DF-gold	1	1 μg	Osteogenesis	N/A	The micro-macro biphasic calcium phosphate (MBCP) granules synergistically enhance the hBMP-2 modRNA-induced osteogenic pathway	[100]

Abbreviations: 5-methylcytidine (5mC); pseudouridine (ψU); 2-thiouridine (2TU).