Abstract: Modulating drug release from liposomes at tumor sites are important for eliciting therapeutic effects of platinum drugs considering their low permeability through liposomal membranes, here a novel secretory phospholipase A₂ (sPLA₂) responsive-liposome system was constructed for oxaliplatin (L-OHP).Lipid ingredients dipalmitoyl phosphatidylcholine and distearoyl phosphoethanolamine-PEG2k, together with facial amphiphiles (FAs) including lithocholic acid (LCA) or 3-keto lithocholic acid (kLCA) were used to prepare sPLA₂ responsive-liposome (LCA-Lip or kLCA-Lip) by thin-film hydration method.The physicochemical properties, sPLA₂-responsive drug release and anti-tumor activity were evaluated in vitro.The results indicated L-OHP loaded liposomes modified with FAs had similar particle sizes of approximately 100 nm and narrow size distributions (PDI < 0.11).Compared with non-FAs-containing liposomes (C-Lip), LCA-Lip or kLCA-Lip has a comparable entrapment efficiency and loading efficiency.LCA-Lip or kLCA-Lip didn't show significant higher drug leakage at the presence of 10% or 50% fetal bovine serum (FBS) in media than that in media without FBS.Treated with secretory phospholipase A₂ from Colo205 cells culture conditioned medium (CCM sPLA₂) for 24 h, FAs modified liposomes released about 70% of carboxyfluorescein (CF), while C-Lip only released 20% of CF.Compared to L-OHP loaded C-Lip, L-OHP-loaded FAs-included formulations had much greater anti-proliferative activity against sPLA₂-secreting Colo205 cells.In summary, our results shows that LCA or kLCA promotes responsiveness of liposomes to tumor-related sPLA₂ and points to a new way to develop platium drugs-loaded liposomal delivery systems with better release mechanisms.