Stimuli-responsive mechanisms are employed for intracellular release of therapeutic cargo.
| Stimulus type | Molecular trigger | Mechanism of release | Responsive DNA origami design element | Cellular target environment | Reported efficacy | References |
|---|---|---|---|---|---|---|
| pH | Acidic endosomal/lysosomal pH (≤ 6.0) | Protonation-induced unfolding of DNA motifs and disruption of gate locks | i-motif DNA, pH-labile triplex-forming sequences | Tumor cells, endosomes | ~85% cargo release in acidic vesicles | [27] |
| Enzyme | MMP-2, MMP-9, Cas3 | Cleavage of peptide crosslinks to trigger nanocage opening | Enzyme-cleavable linkers integrated in hinge designs | Tumor stroma, apoptotic environments | 7× tumor growth suppression vs. control | [28] |
| Redox | High intracellular GSH levels (~10 mM cytosol) | Disulfide bond reduction causes structural disassembly | Disulfide-modified staple strands | Cytosol of cancer cells | > 90% release within 30 min in vitro | [29] |
| Thermal | Mild hyperthermia (42°–45°C) | Thermal denaturation of DNA hybrid regions and gate unlocking | Thermolabile junctions or hairpins | Inflamed or laser-targeted tissues | Controlled burst release in 10 min | [30] |
| Light (NIR/UV) | Photocleavable linkers (e.g., o-nitrobenzyl ester) | Light-induced bond cleavage for remote-controlled release | UV/NIR-responsive chemical gates | Superficial tumors or optically exposed cells | Spatial release precision < 10 µm | [31] |
| Electric field | Localized electric field (> 1 V/cm) | Electrophoretic conformational change or gate disruption | Charge-sensitive switches embedded in a DNA scaffold | On-chip control zones in nanofluidic devices | Sub-second release with field application | [32] |
GSH: glutathione.
DS: Conceptualization, Methodology, Investigation, Writing—original draft, Visualization, Supervision, Project administration. SS: Methodology, Formal analysis, Data curation, Writing—review & editing. NT: Validation, Resources, Writing—review & editing. NB: Supervision, Writing—review & editing, Validation. All authors read and approved the submitted version.
The authors declare that there are no conflicts of interest.
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