final data for SECRIS effect.7z

Up-regulated secretory phospholipase A₂ (sPLA₂) in tumors has been proposed as a stimulus to trigger drug release from liposomes for therapeutic effects. Yet current strategy in developing sPLA₂-responsive liposomes merely considering substrate preference suffers from limited membrane disruptive effects induced by enzymatic hydrolysis and safety issues resulted from overuse of sPLA₂-preferred lipids. Here, a membrane-destabilzing mechanism captilizing on enzymatic extraction and transition of facial amphiphiles (FAs) within lipid membranes was introduced. Enzymatic degradation of FA-modified lipids, a process invovling substrate extraction of lipids out of 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, coined as SECRIS effect. At the presence of sPLA₂, Liposomes containing FA-modified lipids showed enhanced drug release, excellent anti-tumor efficacy and reduced adverse syndromes when delivering oxaliplatin (L-OHP) compared to conventional sPLA₂-liable formulations. Discovery of SECRIS effect paves the road to engineer liposome platforms with high responsiveness and good safety profiles for treatment of sPLA₂-positive tumors.