Abstract
Stimuli-responsive supramolecular systems enable spatiotemporal control of nucleic acid (NA) delivery. To achieve precise and programmable vectors, we designed azobenzene-bridged ionizable amphiphilic Janus glycosides (IAJGs) as single-component, light-responsive DNA carriers. These glucopyranose-based dimers undergo reversible E/Z photoisomerization while forming stable nanocomplexes with plasmid DNA (pDNA). Photoisomerization alters nanocomplex size, surface charge, and internal order, resulting in distinct transfection outcomes. In vitro, O- and S-glycoside derivatives displayed isomer-dependent activity across COS-7, HepG2, and RAW264.7 cells, with pronounced switching effects specially in macrophages. In vivo, systemic administration revealed organ-selective responses: O-glycosides shifted expression from liver to lung upon E → Z conversion, whereas S-glycosides favored spleen targeting. All formulations maintained high cell viability. These results highlight photoswitchable IAJGs as structurally defined vectors for adjustable control over NA delivery and organ tropism.
Data availability
The authors declare that the data supporting the findings of this study related to chemical synthesis, photoswitching studies, and nanocomplex formulation are available within the paper and its Supplementary Information files. The raw data that support the biological findings of this study are available in Zenodo with the identifier https://doi.org/10.5281/zenodo.18223163.
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Acknowledgements
Z.W. gratefully acknowledges China Scholarship Council (CSC) for a doctoral scholarship. G.R.-B. acknowledges funding from the Ministerio de Ciencia, Innovación y Universidades through an FPU fellowship (Grant FPU18/02922). Additional support from the ENS Paris-Saclay Booster Program for mobility is also acknowledged. J.M.G.F. thanks Red de Enfermedades Raras CSIC (RER-CSIC) and PTI+ Salud Global – CSIC for continuous support. C.O.M. also acknowledge the CITIUS (Univ. Seville), for infrastructural support. The authors would like to thank Dr. Cyril Colas from the “Fédération de Recherche” ICOA/CBM (FR2708) for HRMS analysis. This work was supported by the Ministerio de Ciencia, Innovación y Universidades and the Agencia Estatal de Investigación, AEI/10.130 39/501100011033 and “ERDF A way of making Europe” (PID2021-124247OB-C21, PID2021-124247OB-C22, PID2022-141034OB-C21, PID2024-157753OB-C21 and PID2024-157753OB-C22). We also acknowledge funding by the European Union’s Horizon Europe research and innovation program under the Marie Skłodowska-Curie grant agreement 101130235 – Bicyclos.
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Z.W. carried most of the synthesis and the photocharacterization experiments; G.R.-B. and J.M.B. contributed to the synthesis and photocharacterization and also conducted the formulation of the nanococomplexes and their physicochemical characterization; S.M. contributed to curation and analysis of the photochemical data; I.V., I.J.-G., M.J.G., and C.T.deI. performed and analyzed the biological assays; all authors contributed to experimental design, data analysis and manuscript edition; J.M.B., S.M., C.T.deI., C.O.M., J.X., and J.M.G.F. wrote the paper. C.O.M., J.X., and J.M.G.F. devised and supervised the work.
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Wang, Z., Rivero-Barbarroja, G., Benito, J.M. et al. Azobenzene-bridged ionizable amphiphilic Janus glycosides for light-controlled, single-component and organ-modulable pDNA delivery. Commun Chem (2026). https://doi.org/10.1038/s42004-026-01920-z
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DOI: https://doi.org/10.1038/s42004-026-01920-z
