Table 2.

Stimuli responsive delivery systems for proteins and peptides.

Stimuli	Model Protein/Peptide	Responsive Moiety	Mechanism	Delivery System	Reference
pH	Print 3G	Cholesterylhemisuccinate (CHEMS)	CHEMS possesses an inverted cone shape at physiological pH. Under acidic conditions, the carboxylic acid group becomes protonated and CHEMS loses the shape releasing the protein. This transition occurs within endosome where pH is decreased during endocytosis.	Liposomes	[23,36,37]
pH	BSA	PLGA-carboxyl group	Undergoes deprotonation at neutral or basic pH which leads to release of the protein.	Micelles	[38,39]
Enzyme (Human Neutrophil Elastase)	Anti-inflammatory proteins/peptides	HNE-sensitive peptides (Aminobutyric acid, Novarline, Norleucine)	HNE diffuses into the hydrogel and splits the substrate releasing the therapeutic agent into the site of action.	Hydrogel	[17]
Enzyme (Chitosanase)	Fluorescein isothiocyanate-labeled albumin (FITC-albumin)	Chitosan	Enzymatic degradation weakens the capsule wall releasing the protein and the capsule is destroyed over time. Degradation is specific to chitosanase.	Hollow capsules	[40]
Dual Stimuli (pH, Glucose)	Insulin	Concanavalin A, N-(2-(dimethylamino) ethyl)-methacrylamide	Decrease in pH causes ionization of the amino groups causing swelling. Concanavalin A binds glucose, reducing crosslinking density in mycrohydrogels and increasing hydrophilicity leading to swelling then release of Insulin.	Microhydrogel	[41]