Robust Photocleavable Linkers for DNA Synthesis: Enabling Visible Light-Triggered Antisense Oligonucleotide Release in 3D DNA Nanocages Article Swipe
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· 2025
· Open Access
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· DOI: https://doi.org/10.1021/acs.biomac.5c00162
· OA: W4409733439
We synthesized new <i>para</i>-dialkylaminonitrobiphenyl (ANBP) derivatives, s-ANBP and t-ANBP, functionalized with dimethyltrityl and phosphoramidite groups for incorporation into DNA backbones as photocleavable linkers via solid-phase synthesis. Both derivatives exhibited excellent chemical stability under diverse conditions, including acidic, alkaline, and high-salt environments and elevated temperatures. Their incorporation into DNA influenced duplex stability and antisense oligonucleotide (ASO) dissociation efficiency, depending on the number of ANBP units and adjacent nucleotide deletions. The s-/t-ANBP-conjugated DNA showed efficient one-photon photolysis at 415 nm and enhanced two-photon absorption for extended π-system in <i>t</i>-ANBP, with δ<sub>u</sub>Φ<sub>u</sub> values of 1.6 GM (740 nm) and 2.7 GM (800 nm). ANBP-conjugated DNA was used to construct a 3D DNA nanocage capable of light-triggered ASO 4625 release, validated by an <i>in vitro</i> RNA digestion assay, confirming antisense functionality. This platform demonstrates precise, light-mediated therapeutic delivery and offers potential for broader applications in drug delivery and clinical use.
