Morphology, Stability, and Stimuli-Triggered Disassembly of DNA-Containing Polyelectrolyte Complex Micelles: Insights from Experiment and Theory

• Applicant: Professor Dr. Arash Nikoubashman
• Subject Area: Experimental and Theoretical Physics of Polymers ; Statistical Physics, Nonlinear Dynamics, Complex Systems, Soft and Fluid Matter, Biological Physics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566821156

The emergence of DNA and RNA as agents for therapeutics and vaccines has created a pressing need for materials capable of condensing and encapsulating these charged biopolymers into complexes for effective cellular delivery. Polyelectrolyte complex micelles (PCMs), formed by combining DNA conjugates and cationic polymers, are a promising platform for this purpose. The DNA conjugates are synthesized through a straightforward coupling reaction that links negatively charged DNA to a neutral hydrophilic polymer. These conjugates are then combined with polycations to yield nanometer-sized PCMs, composed of a polyelectrolyte complex core and a neutral hydrophilic corona. The PCMs effectively protect the DNA molecules from degradation, and their tunable size and surface properties make them well-suited for facilitating transfection across the negatively charged cell membrane. Despite their promising potential in gene delivery, a fundamental understanding of how macromolecular properties govern PCM morphology, stability, and responsiveness remains lacking. To address this knowledge gap, we will establish in this project fundamental design principles governing PCM formation and disassembly using a combination of experiments and coarse-grained molecular simulations. Specifically, we will systematically investigate how the length and chain architecture of single-stranded DNA-poly(ethylene glycol) (ssDNA-PEG) conjugates and polycations affect PCM morphology and stability. We will further explore the condensation of large DNA molecules through a modified PCM strategy that leverages the hybridization of small DNA conjugate helper molecules to the large DNA targets to create pseudo block copolymers for effective complexation with polycations. We aim to address the key challenge of balancing duplex stability and PCM integrity and explore the option of introducing multiple helper molecules to enhance the compactness of the PCM core. Finally, we will investigate stimuli-responsive PCM disassembly, using environmental triggers such as pH, ion concentration, and temperature to achieve controlled cargo release. In this context, we will quantify the morphological changes of the PCMs during the disassembly process and determine the fate of the disassociated polyelectrolyte chains.

• DFG Programme: Research Grants
• International Connection: South Korea
• Partner Organisation: National Research Foundation of Korea, NRF
• Cooperation Partner: Professorin Dr. Sheng Li