Nanoparticles Escaping RES and Endosome: Challenges for siRNA Delivery for Cancer Therapy

Table 1

Examples of endosomal escape compounds for systemic siRNA delivery.

Category	Compounds	Mechanism of endosomal escape	Compatible with RES evasion	References
Polymers
	Polyethylenimine PEI	Proton sponge effect	Unlikely	[71–73]
	Poly(amidoamine)s (PAAs)	Proton sponge effect	Unknown	[74]
	Charge-reversal copolymers	Proton sponge effect	Unknown	[75–79]
	Poly(propylacrylic acid) (PPAA) and its derivatives	Destabilizing membrane	Unknown	[80–87]
	Amphiphilic cationic copolymers	Hydrophobic interaction and Proton sponge effect	Likely	[88–99]
	pH-sensitive degradable polymers	Increasing endosomal osmotic pressure	Unknown	[100–103]
Lipids
	Cationic lipids	Forming ion pairs with anionic phospholipids within the endosomal membrane	Yes	[104–107]
	Zwitterionic lipids	Forming ion pairs with anionic phospholipids within the endosomal membrane	Likely	[108]
Lipid coated nanoparticles
	Lipid coated calcium phosphate (LCP)	Forming ion pairs and increasing endosomal osmotic pressure	Yes	[109]
	Liposome-polycation-DNA (LPD)	Forming ion pairs and Proton sponge effect	Yes	[32, 34, 35, 110, 111]
Inorganic nanoparticles
	Layered double hydroxide (LDH)	Increasing endosomal osmotic pressure	Unknown	[112]
	Calcium phosphate (CaP)	Increasing endosomal osmotic pressure	Unlikely	[113–116]
	Carbonate apatite (CAp)	Increasing endosomal osmotic pressure	Unlikely	[117]
	Magnesium and manganous phosphate nanoparticles	Increasing endosomal osmotic pressure	Unlikely	[118, 119]
	Calcium carbonate	Increasing endosomal osmotic pressure	Unlikely	[120]
Peptides
	KALA	Destabilizing membrane	Unknown	[121, 122]
	GALA	Destabilizing membrane	Unknown	[123–126]
	Hemagglutinin protein	Destabilizing membrane	Unknown	[127]