Feedback-controlled single-frequency microwave thermal cycling enables dynamic modulation of liposome membrane permeability.

Liposomes are widely used as delivery platforms for therapeutic drugs, nucleic acids, and diagnostic agents. Because cargo release is governed by the permeability of the lipid bilayer, controlling membrane permeability is essential for regulating molecular release from liposomes. Various stimuli, including pH, light, ultrasound, magnetic fields, and temperature, have been explored to control liposomal membrane permeability and cargo release. Among these approaches, microwave (MW) irradiation has also been investigated as a means of modulating liposome permeability, with early studies demonstrating MW-induced drug release and suggesting its potential for controlled molecular release. Recent advances in semiconductor technology have enabled MW systems with improved control over more precise frequency, phase, and irradiation timing. In this study, we investigated a frequency-stable 2.45 GHz MW system combined with real-time temperature feedback to achieve precise temporal control of liposomal thermal history and regulate cargo release. Notably, for DMPC/DOPS liposomes, feedback-controlled repeated temperature cycling across the lipid phase-transition-associated range induced progressively greater leakage, reaching approximately 50% after 20 min. In contrast, conventional heating that maintained the temperature within the transition-associated range resulted in limited leakage. These findings demonstrate that repeated traversal of the phase-transition region, rather than temperature alone, can contribute to enhanced membrane permeability under the tested conditions. These findings indicate that feedback-controlled single-frequency MW irradiation provides a reproducible and programmable approach for regulating liposomal membrane permeability through controlled thermal history, with potential applications in controlled molecular release and membrane transport.