Detachable Cyclic Poly(ethylene glycol)-Embedded Choline Phosphate Liposome Used for Long-Acting and Accurate Cancer Chemo-Immunotherapy with High Security

Liposomes have attracted attention in biomedicine and pharmacy for their benefits including reduced toxicity, extended pharmacokinetics, and biocompatibility. However, their limitations include susceptibility to blood clearance, rapid disintegration, and lack of functionality, restricting their further applications. To address these challenges, inspired by the unique topological features of cyclic polymers and the specific binding property of the choline phosphate (CP) lipid, dipole-dipole interactions between CP molecules are utilized to create a detachable cyclic PEG-embedded CP liposome (d-cycPEG-lipo). In comparison to linear PEG-embedded liposomes (d-linPEG-lipo) and PEGylated liposomes (linPEG-lipo), d-cycPEG-lipo demonstrates enhanced resistance to proteins and macrophages in the bloodstream due to its higher compactness and smoother interface. The packing behavior and lubrication property of cyclic PEG also result in reduced accumulation in organs, leading to an extended pharmacokinetic half-life of 13.6 h. At the tumor site, the PEG embedded in d-cycPEG-lipo detached and facilitated a 3.3-fold higher cell uptake than linPEG-lipo. Notably, d-cycPEG-lipo induces lower inflammation and triggers a stronger immune response than d-linPEG-lipo. In the treatment of breast cancer, d-cycPEG-lipo exhibits a significantly high efficacy of 98.5%. Hence, the reversible combination of cyclic PEG with CP liposomes holds tremendous promise for enhancing drug and antibody delivery in clinical tumor therapy.