Recio-Ruiz Judith, Rycharska Paulina, Grygiel Małgorzata, Michlewska Sylwia, Bryszewska Maria, Ionov Maksim, de la Mata Francisco Javier, García-Gallego Sandra
University of Alcala, Department of Organic and Inorganic Chemistry and Research Institute in Chemistry "Andrés M. Del Río" (IQAR), Madrid 28805, Spain.
University of Lodz, Faculty of Biology and Environmental Protection, Department of General Biophysics, Pomorska 141/143, Lodz 90-236, Poland.
Biomacromolecules. 2025 Aug 11;26(8):4910-4923. doi: 10.1021/acs.biomac.5c00344. Epub 2025 Jul 18.
Gene therapy is a cutting-edge technique for the prevention or treatment of diseases, which demands the development of biocompatible and efficient vectors. Additionally, for cancer therapy, a precise control on the vectors' response at different pH values is required due to the heterogeneity of the tumors' pH. Many nonviral vectors are based on quaternary ammonium compounds, thus exhibiting potential toxicity and persistence. In this work, we designed a new family of cationic carbosilane dendrimers, which exhibits two differential features: a pH-tunable charge, which can modulate the interaction between the nanocarrier and the siRNA, and a cleavable core, which can further enhance the release of the cargo. We thoroughly explored the structural and biophysical characteristics of the new dendrimers at different pH values: 4.5, 5.5, and 7.4. Additionally, biocompatibility in tumoral and nontumoral cells was evaluated along with the hemolytic effect. Finally, we provided a proof-of-concept for their use as pH-responsive nanocarriers of siRNA.
基因治疗是一种用于预防或治疗疾病的前沿技术，这需要开发生物相容性良好且高效的载体。此外，对于癌症治疗而言，由于肿瘤pH值的异质性，需要精确控制载体在不同pH值下的反应。许多非病毒载体基于季铵化合物，因此具有潜在毒性和持久性。在这项工作中，我们设计了一类新型阳离子碳硅烷树枝状大分子，其具有两个不同的特性：一个pH可调电荷，可调节纳米载体与siRNA之间的相互作用；一个可裂解核心，可进一步增强货物释放。我们全面探索了新型树枝状大分子在不同pH值（4.5、5.5和7.4）下的结构和生物物理特性。此外，还评估了其在肿瘤细胞和非肿瘤细胞中的生物相容性以及溶血效应。最后，我们为其作为siRNA的pH响应性纳米载体的应用提供了概念验证。
