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  4. Electrostatic and Hydrophobic Mediation in DNA/Lipid Interactions: Toward the Design of Tailored DNA/Membrane Interfaces
 
doctoral thesis

Electrostatic and Hydrophobic Mediation in DNA/Lipid Interactions: Toward the Design of Tailored DNA/Membrane Interfaces

Wong, Siu Ho  
2025

The interplay of synthetic DNA nanostructures and lipid membranes is an exciting frontier in bioengineering, with the potential to transform synthetic biology and nanomedicine. However, the fundamental principles underlying their interactions-particularly the interplay among hydrophobic anchors, electrostatic forces, and lipid phase behavior-are still not fully understood. This thesis addresses three fundamental questions: (1) How do anchor hydrophobicity and multivalency impact DNA-membrane binding across lipid phases? (2) What design guidelines facilitate predictive engineering of DNA-lipid interfaces? (3) Can ionic conditions be exploited to dynamically tune phase-specific interactions? These questions arise from current gaps in the field (Chapter 1): even though DNA's programmability has led to remarkable progress in membrane engineering, the lack of systematic insights into hydrophobic-electrostatic interplay limits the rational design of robust, adaptive systems. Narrowing these gaps is critical for advancing applications such as targeted drug delivery and synthetic cell engineering, where precise membrane control dictates functional success.

With the goal of addressing these challenges, this thesis employs a reductionist strategy with simplified model systems to identify key variables. A versatile experimental platform is established in Chapter 2 by combining minimal DNA nanostructures with homogeneous and phase-separated lipid vesicle models. Analytical techniques, such as dynamic light scattering, confocal microscopy, and automated image processing, provide qualitative and quantitative measurements for binding affinities and spatial partitioning. Chapter 3 demonstrates that anchor hydrophobicity and multivalency are complementary levers: weak anchors achieve stable binding through multimerization, whereas DNA structural designs enable adaptive reconfiguration on membranes. Chapter 4 extends the findings to phase-separated systems and depicts that strong hydrophobic anchors dictate phase selectivity through chemical properties rather than hydrophobicity alone. It further indicates that divalent cations (Mg2+, Ca2+)stabilize DNA-membrane complexes but homogenize phase specificity, while monovalent ions (Na+) act as secondary modulators. Strong hydrophobic anchors dominate partitioning against competing forces. Balancing hydrophobic and electrostatic affinity is the key to designing phase-selective probes.

Collectively, this thesis crafts a predictive framework for engineering DNA-lipid interfaces, suggesting that anchor chemistry, ionic modulation, and nanostructure design jointly modulate membrane behavior. The insights contribute to the rational design toolbox of DNA-based biomaterials that could benefit lipid raft-targeted drug delivery or building synthetic cell networks. Future work should expand this work by integrating a library of hydrophobic choices (e.g., light-activated anchors), studying kinetic dynamics in more complex systems, and developing multiscale computational models to accelerate a priori biomaterial design. By marrying reductionist rigor with nanotechnology's precision, this work strengthens our capacity to engineer life-inspired systems, bridging the gap between synthetic simplicity and biological complexity.

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Type
doctoral thesis
DOI
10.5075/epfl-thesis-11294
Author(s)
Wong, Siu Ho  

École Polytechnique Fédérale de Lausanne

Advisors
Bastings, Maartje Martina Cornelia  
Jury

Prof. Holger Frauenrath (président) ; Prof. Maartje Martina Cornelia Bastings (directeur de thèse) ; Dr Milena Maria Schuhmacher, Prof. Lorenzo Di Michele, Dr Silvia Hernández Ainsa (rapporteurs)

Date Issued

2025

Publisher

EPFL

Publisher place

Lausanne

Public defense year

2025-07-04

Thesis number

11294

Total of pages

152

Subjects

DNA nanotechnology

•

DNA-lipid interactions

•

hydrophobic anchoring

•

electrostatic bridging

•

multivalency

•

phase-separated membranes

•

selective partitioning

•

synthetic biology

•

membrane nanotechnology

EPFL units
PBL  
Faculty
STI  
School
IMX  
Doctoral School
EDMX  
Available on Infoscience
June 30, 2025
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/251737
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