Posted by The study investigates the effectiveness of a cationic cyclodextrin polymer-based delivery system for intracellular transport of RNA molecules. Efficient delivery of nucleic acids such as small interfering RNA (siRNA) and messenger RNA (mRNA) remains one of the main challenges in modern gene therapy, primarily because these molecules are unstable, negatively charged, and unable to easily cross cellular membranes.
To address this challenge, the authors compared a cationic quaternary ammonium β‑cyclodextrin polymer (QABCDPS) with polyethylenimine (PEI), a widely used but often cytotoxic polymer.
The research focused on evaluating both polymers in terms of RNA binding capacity, physicochemical properties, cellular uptake, and cytotoxicity. Polyplexes were prepared at various nitrogen phosphate (NP) ratios. Their size and surface charge were analyzed using dynamic light scattering and zeta potential measurements, while biological performance was assessed through cell-based experiments including confocal microscopy and flow cytometry.
The results demonstrated that both polymers were capable of forming stable polyplexes with siRNA and mRNA, but their performance differed significantly. PEI showed strong nucleic acid binding and efficient cellular internalization, which is consistent with its well-known function as a highly effective transfection agent. However, this advantage was accompanied by considerable cytotoxicity, which limits its practical application in therapeutic contexts.
In contrast, the cyclodextrin polymer (QABCDPS) exhibited lower cytotoxicity while still maintaining a satisfactory RNA-loading capacity. Although its transfection efficiency was somewhat lower than that of PEI, it provided a more favorable safety profile, making it a promising alternative for applications where reduced toxicity is critical.
An important aspect of the study was the comparison between siRNA and mRNA delivery. The findings suggested that both polymers handle these two types of RNA differently due to their size and structural differences. mRNA molecules are significantly larger and more complex than siRNA, which affects the stability and formation of polyplexes as well as their intracellular behavior. The authors observed that optimizing formulation parameters, such as the NP ratio, is essential to achieve efficient delivery depending on the type of RNA used.
Microscopy and flow cytometry analyses confirmed successful cellular uptake of the polyplexes and indicated that intracellular distribution patterns vary depending on the carrier system. These observations further support the idea that carrier design plays a crucial role not only in delivery efficiency but also in the biological outcome of the transported nucleic acids.
In conclusion, the study highlights the trade-off between efficiency and toxicity in polymer-based gene delivery systems. While PEI remains a highly efficient carrier, its cytotoxicity is a major limitation. The quaternary ammonium β‑cyclodextrin polymer offers a promising balance between safety and performance, especially for applications requiring repeated administration or sensitive cell types. Overall, the research contributes to the development of safer and more effective nonviral RNA delivery platforms, which are essential for advancing gene therapy and RNA-based therapeutics.
Rusznyák, Á.; Magyar, P.; Dajka, V.; Gyöngyösi, A.; Lekli, I.; Vámosi, G.; Malanga, M.; Fenyvesi, É.; Szente, L.; Váradi, J.; et al. Comparison of the siRNA and mRNA Carrying Capacity of Quaternary Ammonium β-Cyclodextrin Polymer and Polyethylenimine. Pharmaceutics 2026, 18, 713. https://doi.org/10.3390/pharmaceutics18060713