Table 1.

Summary of carriers for controlled activation of CPPs

Mechanism of Activation	System Description	Cell-Penetrating Peptide	Activation Trigger	Cargo	Ref
Controlled display of CPPs by removal of “stealth” polymers	TAT-functionalized liposomes with cleavable PEG coating	YGRKKRRQRRR	pH sensitive cleavage of hydrazone linker for PEG release	Rhodamine as model cargo	59,60
				GFP plasmid as model gene cargo	61
				Chemotherapeutic doxorubicin	62
	Human transcriptional factor Hph-1-functionalized quantum dots with cleavable PEG coating	YARVRRRGPRR	MMP-2 cleavage of peptide linker for PEG release	Quantum dot for fluorescent imaging	63
	Arginine-rich CPP-functionalized dextran-coated iron oxide particles with cleavable PEG coating	RRRRGRRRRKG	MMP-2 cleavage of peptide linker for PEG release	Iron oxide particle for MR imaging	65
	TAT-functionalized liposomes with cleavable PEG coating	YGRKKRRQRRR	MMP-2 cleavage of peptide linker for PEG release	Rhodamine as model cargo	66
	TAT-functionalized micelle with dissociable PEG coating	YGRKKRRQRRR	pH sensitive dissociation of polysulfonamide-PEG for PEG release	FITC as model cargo	67
				Chemotherapeutic doxorubicin	68
	TAT-functionalized liposome with cleavable PEG coating	AYGRKKRRQRRR	Cysteine-mediated cleavage of disulfide linker for PEG release	Calcein as model cargo	69
				DiR and DiD as model cargo	70
Controlled exposure of CPPs by actuation of molecular tethers	TAT-functionalized micelles with ionizable linkers for triggered CPP display	YGRKKRRQRRR	pH sensitive extension of linker beyond PEG coating for TAT presentation	Chemotherapeutic doxorubicin	72
Controlled presentation of CPPs by dissociation from ionic inhibitors	Arginine8 with cleavable anionic inhibitory domain	RRRRRRRR	Prostate-specific antigen cleavage of peptide linker for dissociation of anionic inhibitor domain	FITC as model cargo	74
			MMP-14 cleavage of peptide linker for dissociation of anionic inhibitor domain	Technetium-99m for SPECT imaging	78
	Arginine9 with cleavable anionic inhibitory domain	RRRRRRRRR	MMP-2 cleavage of peptide linker for dissociation of anionic inhibitor domain	Fluorescein and Cy5 as model cargo	54, 73, 75
			MMP-2/9 cleavage of peptide linker for dissociation of anionic inhibitor domain	177Lu and 126I for PET/SPECT imaging	79
	Arginine9-functionalized dendrimeric nanoparticle with cleavable anionic inhibitor domains	RRRRRRRRR	MMP-2 cleavage of peptide linker for dissociation of anionic inhibitor domain	Cy5 and gadolinium for fluorescent and MR imaging	76,77
	Arginine5 with cleavable anionic inhibitory domains	RRRRR	MMP-2 cleavage of peptide linker for dissociation of anionic inhibitor domain	BQH3 and Alexa750 for photoacoustic imaging	80
	TAT-functionalized asparaginase with ionic-associated heparin inhibitor	YGRKKRRQRRR	Competitive binding of protamine for dissociation of heparin inhibitor	Anti-tumor asparaginase enzyme	81,83
	Penetratin-functionalized HPMA polymer with cleavable inhibitory neutralizing groups	RRMKWKK	UV light cleavage of linker for dissociation of neutralizing groups	(KLAKLAK)2 proapoptotic peptide	84
Controlled charge of CPPs by ionizable residues	Modified transportan with lysine→histidine substitutions	AGYLLGHINLHHL-AHLHHIL	Ionization of histidine residues below pKa of 6.5	Chemotherapeutic camptothecin	85
Controlled density of CPPs by temperature-triggered micelle assembly	Arginine5-functionalized elastin-like polypeptide diblock copolymers	RRRRR	Hyperthermia-triggered micelle assembly for modulation of arginine density	Alexa488 as model cargo	89