Authors: Friederike Schmid, Jiajia Zhou, Jonas Lehnen, David Noel Zimmer, Giovanni Settanni
Electrostatic interactions play a central role in RNA/DNA delivery, yet their molecular-level consequences remain difficult to probe experimentally. Here, we use molecular simulations to explor how charge interactions shape the assembly and performance of two major classes of delivery vehicles: Polyplexes and lipid nanoparticles.
For polyplexes, where charge-–charge interactions drive self-assembly, we simulate complexes formed by a single DNA molecule and block ionomers containing cationic and neutral hydrophilic blocks. The results show that ionomer sequence strongly affects polyplex compactness and microstructure, offering a possible explanation for experimentally observed differences in transfection efficiency [1]. We further find that the overall charge ratio between polyelectrolytes and RNA/DNA is the dominant factor determining polyplex composition. Near the isoelectric point, polyplexes form large aggregates, whereas away from it, smaller assemblies and even single-RNA complexes become accessible [2]. These trends are consistent with experimental observations in systems such as polyethylenimine with self-amplifying RNA.
In lipid nanoparticles, electrostatics govern both RNA binding and drug release. Our simulations reveal that the effective interactions between ionizable lipids and RNA switch from attractive to repulsive with pH [3], providing a potential trigger for release. Furthermore, we identify by which mechanisms electrostatic lipid–lipid interactions can promote lipid phase transitions that facilitate RNA escape [4].
Together, these findings highlight how charge interactions influence structure, stability, and release in RNA/DNA delivery systems.
References:
[1] The influence of block ionomer microstructure on polyplex properties: Can simulations help to understand differences in transfection efficiency?
P. Heller, B. Weber, J. Zhou, D. Hobernik, M. Bros, F. Schmid, M. Barz, Small 13, 1603694 (2017).
doi:10.1002/smll.201603694
[2] Assembly of polyplexes for RNA delivery
J. Lehnen, J.M. Herrero, H. Haas, F. Schmid, G. Settanni, ChemRxiv preprint (2025).
doi: 10.26434/chemrxiv-2025-k40pn
[3] pH-Dependent Behavior of Ionizable Cationic Lipids in mRNA-Carrying Lipoplexes Investigated by Molecular Dynamics Simulation
G. Settanni, W. Brill, H. Haas, F. Schmid, Macrom. Rapid Comm. 43, 2100683 (2022).
Doi: 10.1002/marc.202100683
[4] Transient interactions between cationic ionizable lipids and anionic lipids foster lamellar to hexagonal phase transition
D.N. Zimmer, F. Schmid, G. Settanni, ChemRxiv preprint (2025).
doi: 10.26434/chemrxiv-2025-rwb