Unraveling the Mechanism of PEG-Enhanced Ultrasound-Triggered Release from Liposomes
I. Simón Grau (TU Delft - Applied Sciences)
Farzaneh Gholamianpour (Student TU Delft)
Lassi V. Tiihonen (TU Delft - Applied Sciences)
Simon Vliek (Student TU Delft)
Amber Renkema (Student TU Delft)
Teun L.A. Janssen (TU Delft - Electrical Engineering, Mathematics and Computer Science)
Coen Fransen (TU Delft - RID/TS/Technici Pool)
Steven R. Parnell (ISIS Neutron and Muon Source)
R. Alessandri (Katholieke Universiteit Leuven)
Remco Hartkamp (TU Delft - Mechanical Engineering)
Wim G. Bouwman (TU Delft - Applied Sciences)
Tiago L. da Costa (TU Delft - Electrical Engineering, Mathematics and Computer Science)
Alina Y. Rwei (TU Delft - Applied Sciences)
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Abstract
Ultrasound-responsive liposomes represent a promising strategy for the targeted delivery of therapeutic agents to deep tissues, combining the clinically validated biocompatibility of liposomes with precise spatiotemporal control via ultrasound. While the incorporation of polyethylene glycol-conjugated lipids into liposomal formulations has long been known to enhance ultrasound-triggered release, the mechanistic basis of this enhancement remains poorly understood, hindering the rational design of formulations with enhanced ultrasound-triggered release. To address this, we investigated the proposed hypotheses in the literature, including the influence of the packing parameter, differences in thermal, mechanical, and fluidity properties, as well as structural changes such as micelle formation or bilayer thinning for stealth liposomes containing polyethylene glycol, polycarboxybetaine, or polysarcosine. Our results indicate that PEG-enhanced ultrasound-triggered release cannot be attributed to changes in bulk bilayer properties, including the packing parameter, membrane mechanics, thermal behavior, or fluidity. Moreover, the membrane structure remained unchanged after insonation, with no evidence of micelle ejection or membrane thinning. Instead, experiments and computational simulations suggest that polyethylene glycol-conjugated lipopolymers facilitate sonoporation by rearranging into micelle-like structures at the periphery of ultrasound-induced pores in the lipid bilayer, enabled by their low critical micelle concentration, thereby enhancing the release through these transient openings. Finally, we discuss how these insights could be extended beyond polyethylene glycol lipopolymers to guide the design of liposomes with enhanced ultrasound-triggered release, by shifting optimization from bulk bilayer properties to a sonoporation-oriented framework that integrates computational screening, AI-enabled formulation design, and ultrasound waveform considerations.
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