I. Simón Grau | TU Delft Repository

Ultrasound-responsive liposomes: A mechanistic framework to decode the effects of acoustic parameters

Journal article (2026) - I. Simón Grau, R.F.A. van den Elshout, G.K. Wardhana, M. Aqamolaei, Isabella S.T. de Jonge, Remco Hartkamp, R. Alessandri, Tiago L. Costa, A.Y. Rwei

Ultrasound offers a noninvasive, clinically relevant means to achieve precise spatiotemporal control of cargo release from ultrasound-responsive drug delivery systems within deep tissues. This approach enables targeted delivery of therapeutic agents, enhancing efficacy while minimizing systemic toxicity. While previous studies show that release from ultrasound-responsive liposomes depends on acoustic parameters, the underlying mechanisms remain unclear. A deeper mechanistic understanding is essential to achieve precision over release and maximize therapeutic outcomes. To address this, we propose a sonoporation-based framework to describe release dynamics across varying frequencies, pressures, duty cycles, and pulse repetition frequencies for ultrasound-responsive poly(ethylene glycol)-functionalized liposomes. Using computational simulations validated by empirical results, our framework identifies a critical pressure threshold for release onset and demonstrates how the time spent above this threshold, modulated by acoustic parameters, governs release efficiency. To elucidate these effects, custom-built ultrasound transducers with different resonance frequencies were fabricated and characterized to ensure precise sample alignment, minimize acoustic distortion, and maintain a controlled focal-volume-to-sample-volume ratio across different frequencies. COMSOL simulations indicated that oscillatory acoustic pressure plays a more dominant role than acoustic radiation force, while coarse-grained molecular dynamics simulations captured pressure-dependent pore formation dynamics within the lipid bilayer. Together, our experiments and simulations highlight mechanical effects—particularly oscillatory acoustic pressure—as the primary driver of sonoporation-facilitated release. Finally, we discuss how optimizing acoustic parameters through this mechanistic framework could facilitate safe and effective clinical translation by considering tissue safety and ultrasound transducer design. ...

Ultrasound offers a noninvasive, clinically relevant means to achieve precise spatiotemporal control of cargo release from ultrasound-responsive drug delivery systems within deep tissues. This approach enables targeted delivery of therapeutic agents, enhancing efficacy while minimizing systemic toxicity. While previous studies show that release from ultrasound-responsive liposomes depends on acoustic parameters, the underlying mechanisms remain unclear. A deeper mechanistic understanding is essential to achieve precision over release and maximize therapeutic outcomes. To address this, we propose a sonoporation-based framework to describe release dynamics across varying frequencies, pressures, duty cycles, and pulse repetition frequencies for ultrasound-responsive poly(ethylene glycol)-functionalized liposomes. Using computational simulations validated by empirical results, our framework identifies a critical pressure threshold for release onset and demonstrates how the time spent above this threshold, modulated by acoustic parameters, governs release efficiency. To elucidate these effects, custom-built ultrasound transducers with different resonance frequencies were fabricated and characterized to ensure precise sample alignment, minimize acoustic distortion, and maintain a controlled focal-volume-to-sample-volume ratio across different frequencies. COMSOL simulations indicated that oscillatory acoustic pressure plays a more dominant role than acoustic radiation force, while coarse-grained molecular dynamics simulations captured pressure-dependent pore formation dynamics within the lipid bilayer. Together, our experiments and simulations highlight mechanical effects—particularly oscillatory acoustic pressure—as the primary driver of sonoporation-facilitated release. Finally, we discuss how optimizing acoustic parameters through this mechanistic framework could facilitate safe and effective clinical translation by considering tissue safety and ultrasound transducer design.

Unraveling the Mechanism of PEG-Enhanced Ultrasound-Triggered Release from Liposomes

Journal article (2026) - I. Simón Grau, Farzaneh Gholamianpour, Wim G. Bouwman, Tiago L. da Costa, Alina Y. Rwei, Lassi V. Tiihonen, Simon Vliek, Amber Renkema, Teun L.A. Janssen, Coen Fransen, Steven R. Parnell, R. Alessandri, Remco Hartkamp

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. ...

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.

Miniaturized therapeutic systems for ultrasound-modulated drug delivery to the central and peripheral nervous system

Review (2024) - Pancheng Zhu, Ignasi Simon, Ida Kokalari, Daniel S. Kohane, Alina Y. Rwei

Ultrasound is a promising technology to address challenges in drug delivery, including limited drug penetration across physiological barriers and ineffective targeting. Here we provide an overview of the significant advances made in recent years in overcoming technical and pharmacological barriers using ultrasound-assisted drug delivery to the central and peripheral nervous system. We commence by exploring the fundamental principles of ultrasound physics and its interaction with tissue. The mechanisms of ultrasonic-enhanced drug delivery are examined, as well as the relevant tissue barriers. We highlight drug transport through such tissue barriers utilizing insonation alone, in combination with ultrasound contrast agents (e.g., microbubbles), and through innovative particulate drug delivery systems. Furthermore, we review advances in systems and devices for providing therapeutic ultrasound, as their practicality and accessibility are crucial for clinical application. ...