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.

Hypothesis: Pea proteins can act not only as interfacial stabilizers of oil-in-water emulsions but also as gelling agents in the continuous phase. Protein gelation, rather than droplet jamming, may be the main mechanism of emulsion stability, providing a physical explanation for the creaminess of high-protein plant-based emulsions. Experimental: Spin-echo small angle neutron scattering (SESANS) with D₂O/H₂O contrast variation was used to study 15% pea protein dispersions and emulsions with 40–60% rapeseed oil, 7.5% protein at pH 3 to 6.5. SESANS investigates length scales up to tens of micrometres, enabling simultaneous analysis of protein networks and oil droplets without dilution. Complementary small angle X-ray/neutron scattering were used to validate protein aggregate size, and hydration. Findings: Protein dispersions at neutral pH formed mass fractal networks with small individual building blocks (radius ∼38 Å, hydration ∼70%). Emulsions consisted of oil droplets embedded in these networks, with droplet radii decreasing at higher oil fractions due to an effective higher protein concentration in the continuous phase, creating a denser network. Dispersions and emulsions at lower pH contained aggregated clusters of denatured proteins. These coarse and inhomogeneous networks gave increasing droplet radii at lower pH. Contrast variation enabled the separation of protein and oil droplet scattering, demonstrating that protein gelation rather than droplet jamming is the main mechanism of stability. This gives a physical explanation of the high viscosity of high-protein plant-based emulsions and is promising for these plant materials to be used as gelling agents in food applications.