Rodríguez-Franco Hugo J, Kononenko Artem, Bastings Maartje M C
Programmable Biomaterials Laboratory, Institute of Materials, Interfaculty Bioengineering Institute, School of Engineering, Ecole Polytechnique Fédérale Lausanne, Lausanne 1015, Switzerland.
ACS Polym Au. 2025 May 22;5(4):343-352. doi: 10.1021/acspolymersau.5c00012. eCollection 2025 Aug 13.
DNA origami nanoparticles (DONs) hold great potential for interacting with biological systems, yet their applicability is limited by nuclease activity and challenging ionic conditions in biological environments. Among various stabilization strategies, oligolysine-PEG coatings have emerged as a preferred option due to their straightforward implementation and protective capacity. However, their static nature restricts compatibility with dynamic DON systems and may hinder the functional availability of preincorporated bioactive cues. Here, we introduce a strategy to confer responsiveness to these coatings by incorporating labile disulfide bridges at defined positions within the oligolysine segments. Upon exposure to the characteristic reductive conditions of the cellular cytoplasm, these linkers undergo cleavage, weakening the multivalent electrostatic interactions between the coatings and DONs. Through the synthesis and characterization of distinct oligolysine-PEG variants with varying degrees of peptide segmentation, we confirm their ability to protect DONs under physiological conditions while enabling efficient decomplexation in reductive environments, observing differences in DON functional recovery depending on the number and positioning of the linkers. This work provides a foundation for developing responsive oligolysine-PEG coatings, broadening the functional scope and biomedical applicability of stabilized DONs.
DNA折纸纳米颗粒（DONs）在与生物系统相互作用方面具有巨大潜力，但其适用性受到生物环境中核酸酶活性和具有挑战性的离子条件的限制。在各种稳定策略中，寡聚赖氨酸-聚乙二醇涂层因其实施简单和保护能力而成为首选。然而，它们的静态性质限制了与动态DON系统的兼容性，并可能阻碍预先掺入的生物活性线索的功能可用性。在此，我们引入一种策略，通过在寡聚赖氨酸片段内的特定位置引入不稳定的二硫键，赋予这些涂层响应性。暴露于细胞质的特征性还原条件下，这些连接子会发生裂解，削弱涂层与DONs之间的多价静电相互作用。通过合成和表征具有不同程度肽段分割的不同寡聚赖氨酸-聚乙二醇变体，我们证实它们在生理条件下保护DONs的能力，同时在还原环境中实现高效解聚，并观察到取决于连接子数量和位置的DON功能恢复差异。这项工作为开发响应性寡聚赖氨酸-聚乙二醇涂层奠定了基础，拓宽了稳定化DONs的功能范围和生物医学适用性。
