Azobenzene-bridged ionizable amphiphilic Janus glycosides for light-controlled, single-component and organ-modulable pDNA delivery

TL;DR

Researchers developed light-sensitive DNA delivery carriers that can change their behavior with light, allowing precise control over where and when DNA is delivered in the body.

Contribution

The novel contribution is the design of azobenzene-bridged glycosides that enable light-controlled DNA delivery with organ-specific targeting.

Findings

Light-induced photoisomerization alters nanocomplex properties and transfection outcomes in different cell types.

O-glycosides shift gene expression from liver to lung upon light exposure, while S-glycosides target the spleen.

All formulations showed high cell viability across tested cell lines and macrophages.

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.

Stimuli-responsive supramolecular systems offer innovative solutions for precise nucleic acid delivery, addressing the need for spatiotemporal control. Here, the authors develop azobenzene-bridged ionizable amphiphilic Janus glycosides as light-responsive DNA carriers, demonstrating reversible photoisomerization that modulates transfection outcomes and organ targeting.

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