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Utilizing liposomes for drug delivery is a vital technology in modern nanomedicine. Equipping liposome surfaces with peptides as trigger-responsive release units enables smart, precision-controlled drug delivery. However, peptide–membrane interactions have largely been studied as separate entities ("binary systems"). When membrane-active peptides are directly conjugated onto liposomes ("unary systems"), the constructs often become highly unstable, causing premature drug leakage—an enduring bottleneck in the field. 

The research team led by Dr. Hsien-Ming Lee at the Institute of Chemistry, Academia Sinica, identified a solution by screening membrane-lytic peptides. They discovered that Magainin 2, a peptide derived from the African clawed frog, exhibits a unique dual behavior. While inert toward zwitterionic liposomes in binary systems, it becomes strongly lytic in unary configurations. This unexpected property enables a balance between encapsulation stability and efficient triggered release, makes Magainin 2 an excellent backbone for trigger-responsive peptide. Using cryo-electron microscopy, small-angle X-ray scattering, and fluorescence-lifetime imaging, the team visualized the dynamic mechanism: upon stimulation, the surface-conjugated peptides rapidly activate, aggregate, and form membrane defects, enabling controlled release. This finding redefines design principles for trigger-responsive peptidyl liposomes. The research has been published on February 18, 2026 in Journal of the American Chemical Society.

The first author is Dr. Hua-De Gao (Institute of Chemistry, Academia Sinica; Ph.D. from Department of Chemistry, National Taiwan University), with collaborative support from cryo-electron tomography (Dr. Meng-Chiao Ho, Institute of Biological Chemistry, Academia Sinica), small-angle X-ray scattering (Prof. U-Ser Jeng and Prof. Chun-Jen Su, National Synchrotron Radiation Research Center). The research was supported by the Academia Sinica iMATE Program and NSTC.