Understanding, mimicking, and exploiting lipid membrane fusion in biomedicine and synthetic biology

Lipid membrane fusion is a fundamental process underlying numerous biological functions in both physiological and pathological conditions. Understanding the physico-chemical mechanisms governing fusion, from the minimal molecular and structural requirements to the factors regulating its progression, is essential for elucidating complex biological phenomena and developing new biomedical and synthetic biology strategies. In this review, we adopt an interdisciplinary perspective to analyze how lipid composition, environmental conditions, and fusogenic agents influence the different stages of the fusion process, from membrane docking to fusion pore formation. We critically examine the main in vitro membrane models, discussing their advantages and limitations, and integrate experimental results with contributions from molecular simulations, which have allowed us to resolve the fusion intermediates and the underlying energy landscape at the nanoscale level. Particular emphasis is placed on synthetic fusogenic agents, including peptides, nucleic acids, nanoparticles, and polymers, highlighting their mechanisms of action and possibilities for rational design. Finally, we discuss emerging applications of membrane fusion in synthetic biology and biomedicine, with a focus on biomimetic systems, controlled drug delivery, and fusogenic lipid particles that promote endosomal escape. Overall, this review aims to provide a unifying conceptual framework linking fundamental principles of membrane fusion with advanced technological applications.