Facial Amphiphile-Modified Lipids Highly Sensitize Liposomes toward Secretory Phospholipase A₂

Upregulated secretory phospholipase A₂ (sPLA₂) in tumors has been proposed as a stimulus to trigger drug release from liposomes for therapeutic effects. However, the current strategy for developing sPLA₂-responsive liposomes merely considering substrate preference suffers from limited membrane disruptive effects induced by enzymatic hydrolysis and safety issues resulting from the overuse of sPLA₂-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 <i>sn-2</i> ester bonds by sPLA₂, rotation, and interface settling of detached FAs, caused tremendous efflux of payloads from liposomes, termed the SECRIS effect. In the presence of sPLA₂, 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 sPLA₂-labile formulations. The discovery of the SECRIS effect creates a new pathway to engineer liposome platforms for the treatment of sPLA₂-positive tumors.