Publication
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.