Facial Amphiphile-Modified Lipids Highly Sensitize Liposomes toward Secretory Phospholipase A.

Upregulated secretory phospholipase A (sPLA) in tumors has been proposed as a stimulus to trigger drug release from liposomes for therapeutic effects. However, the current strategy for developing sPLA-responsive liposomes merely considering substrate preference suffers from limited membrane disruptive effects induced by enzymatic hydrolysis and safety issues resulting from the overuse of sPLA-preferred lipids. Here, a membrane-destabilizing mechanism based on enzymatic extraction and the transition of facial amphiphiles (FAs) within lipid membranes was introduced. Enzymatic degradation of FA-modified lipids, a process involving substrate extraction of lipids from membranes and cleavage of ester bonds by sPLA, rotation, and interface settling of detached FAs, caused tremendous efflux of payloads from liposomes, termed the SECRIS effect. In the presence of sPLA, oxaliplatin (L-OHP) loaded liposomes containing FA-modified lipids showed enhanced drug release, comparable in vitro cytotoxicity, and excellent in vivo antitumor efficacy and reduced adverse syndromes in Colo205-bearing mice compared to conventional sPLA-labile formulations. The discovery of the SECRIS effect creates a new pathway to engineer liposome platforms for the treatment of sPLA-positive tumors.