Micromanaging cardiac regeneration: Targeted delivery of microRNAs for cardiac repair and regeneration

Table 1 MicroRNAs involved in cardiomyocytes differentiation

microRNA	Targets	Effect on cardiomyogenesis (mechanism)	Used in reprogramming	Ref.
Increased during cardiomyogenesis
1	Dll1 (Notch)	↑ CM Differentiation (↑ Nkx2.5 and Myogenin)	+	[102-104,106,109-111]
	Hes1 (Notch)	↑ CM Differentiation (↑ Nkx2.5 and GATA4)
	Hand2	↓ CM Proliferation
	HDAC4	↑ CM Differentiation (↑ Mef2c)
	Myocardin	↑ CM Maturation (↓ SMC phenotype)
30a-e	Snai2	↑ CM Differentiation (↓ mesenchymal genes)	-	[102,103,120]
	Smarcd2	↑ CM Differentiation (↓ mesenchymal genes)
	Tnrc6a	↑ CM Maturation (↓ miR-206: ↓ SMC Phenotype)
133a-b	Snai1	↑ CM Differentiation (↓ mesenchymal genes)	+	[102-105,113]
	SRF	↓ CM Proliferation
	Cyclin D2	↓ CM Proliferation
181a-d	?	↑ CM Proliferation	-	[103,175]
195	Cyclin D1	↓ CM Proliferation	-	[102,103,119,176]
	HMGA	↓ CM Differentiation (↓ Nkx2.5)
208b	Myostatin	↑ CM Proliferation	+	[103,114,117,118]
	Sox6, Purβ	↑ CM Maturation (↑ beta-Myosin Heavy Chain)
	THRAP1	↑ CM Maturation (↑ beta-Myosin Heavy Chain)
499-5p	? (↑ Wnt)	↑ CM Differentiation (↑ Nkx2.5, Mef2c and GATA4)	+	[102,103,115]
Decreased during cardiomyogenesis
31	?	?	-	[103]
34c-3p	?	?	-	[103]
151-3p	ATP2a2	↓ CM Maturation (↓ beta-Myosin Heavy Chain)	-	[103,177]
221	?	?	-	[103]
222	?	?	-	[103]

ATP2a2: Sarcoplasmic reticulum Ca²⁺ ATPase 2; CM: Cardiomyocyte; Dll1: Delta-like 1; GATA4: GATA Binding Protein 4; Hand2: Heart and neural crest derivatives expressed 2; HDAC4: Histone deacetylase 4; Mef: Myocyte enhancer factor; miR: MicroRNA; Nkx2.5: NK2 homeobox 5; Purβ: Purine-rich element binding protein beta; Smarcd2: SWI/SNF related matrix associated actin dependent regulator of chromatin subfamily d member 2; SMC: Smooth muscle cell; Snai: Snail family zinc finger; Sox6: Sex determining region Y-box 6; SRF: Serum response factor; THRAP1: Thyroid hormone receptor associated protein 1; Tnrc6a: Trinucleotide repeat-containing gene 6A; Wnt: Wingless-type MMTV integration site family.

Table 2 Characteristics of particulate drug delivery systems

Carrier	Size range (nm)	Preparation method	Advantages for drug delivery	Disadvantages for drug delivery	Ref.
Liposomes and polymerosomes	10-2000	Self-assembly in aqueous solutions	High drug-carrying capacity Good for hydrophobic and hydrophilic drugs Surface functionalization possible Simple preparation	Batch-to-batch variability Difficulties in sterilization	[123,135,138,141,143,150,161,178]
Microbubbles	10-1000	Various depending on type	Surface functionalization possible	Not good for hydrophobic drugs Low drug-carrying capacity	[145-148,166,168,179]
Polymeric micelles	10-100	Direct organization or controlled aggregation in solvent	Long blood circulation time Surface functionalization possible Simple preparation	Not good for hydrophobic drugs Low drug-carrying capacity	[123,136,137,155,158]
Nanoparticles and nanospheres	10-100	Nanoparticles: Polymerization of monomers by emulsion Nanospheres: Interfacial polymerization and phase inversion with polymeric emulsions	Shape, size and mechanical properties tunable Possibility for controlled release	Toxicity of residual chemicals from preparation process Limited cellular uptake and degradation	[123,126,128,139,150,151,155,180]
Dendrimeres	1-10	Convergent or divergent synthesis	High functionalized surface	Difficult preparation process Toxicity	[123,154,156]