Enzyme-responsive liposomes for controlled drug release

Compared to other nanovectors, liposomes exhibit unique advantages, such as good biosafety and high drug-loading capacity. However, slow drug release from conventional liposomes makes most payloads unavailable, restricting the therapeutic efficacy. Therefore, in the last ∼20 years, enzyme-responsive liposomes have been extensively investigated, which liberate drugs under the stimulation of enzymes overexpressed at disease sites. In this review, we elaborate on the research progress on enzyme-responsive liposomes. The involved enzymes mainly include phospholipases, particularly phospholipase A2, matrix metalloproteinases, cathepsins, and esterases. These enzymes can cleave ester bonds or specific peptide sequences incorporated in the liposomes for controlled drug release by disrupting the primary structure of liposomes, detaching protective polyethylene glycol shells, or activating liposome-associated prodrugs. Despite decades of efforts, there are still a lack marketed products of enzyme-responsive liposomes. Therefore, more efforts should be made to improve the safety and effectiveness of enzyme-responsive liposomes and address the issues associated with production scale-up.