Institute of Chemistry, Academia Sinica – Research

Utilizing liposomes for drug delivery is a vital technology in modern nanomedicine. Equipping the liposome surface with "peptides" to act as signal transducers works much like a trigger, enabling diverse and smart precision-release designs. However, the molecular interactions between peptides and liposomal membranes following chemical conjugation are highly complex, with related mechanisms remaining largely unknown. In past studies, scientists mostly studied peptide-liposome interactions as two chemical entities, which is known as a "binary system". Yet, once a membrane-active peptide is directly conjugated to the liposome surface (forming a "unary system"), peptide-modified liposomes often become highly unstable, leading to premature drug leakage—this encapsulation stability issue has been a major bottleneck that is difficult to overcome.

To break through this dilemma, the research team led by Associate Research Fellow Hsien-Ming Lee at the Institute of Chemistry, Academia Sinica, systematically screened various membrane-lytic peptides. The goal was to find an ideal peptide backbone that maintains liposome stable in the signal waiting state and activates precisely upon receiving a signal, while simultaneously elucidating its key interaction mechanisms with the liposome membrane. The research team discovered that an antimicrobial peptide (AMP) secreted from the skin of the "African clawed frog" was the key to this breakthrough. In binary systems, this peptide exhibits almost no destructive power against liposomes; however, in a unary system, it demonstrates powerful functionality. Through a specialized chemical masking design, it is currently the only AMP backbone capable of remaining fully inert when masked on the surface without inducing leakage, while activating its membrane-lytic activity upon receiving a signal, successfully balancing liposome encapsulating stability and release efficiency.

By employing cutting-edge techniques such as cryo-electron microscopy, small-angle X-ray scattering, and fluorescence-lifetime imaging microscopy, the research team clearly captured the dynamic processes of this microscopic world. When this smart peptidyl liposome receives a triggering signal, the surface peptides are immediately awakened, moving and gradually aggregating on the membrane surface, and then creating a membrane defect to release the drug. This discovery redefines the design principles of trigger-responsive peptidyl liposomes, and is expected to significantly enhance the feasibility of clinical peptide-modified liposome for precision drug delivery in the future.

The first author of this study is Dr. Hua-De Gao (currently a postdoctoral researcher at the Institute of Chemistry, Academia Sinica, and originally a Ph.D. student at the Department of Chemistry, National Taiwan University). The research integrated cross-disciplinary technologies, including cryo-electron tomography (Prof. 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), and technical assistance from the Mass Spectrometry and Imaging core facilities at the Institute of Chemistry and the Academia Sinica Cryo-EM Facility. This study gratefully acknowledges financial support from the Academia Sinica iMATE Program and the National Science and Technology Council (NSTC). The research findings were published in the Journal of the American Chemical Society on February 18, 2026.