Azobenzene-Cored Amphiphilic Dendrimers: Molecular Photoswitching Controls Dendriplex Topology and Gene Delivery

Azobenzene-cored ionizable amphiphilic Janus dendrimers (Azo-IAJDs) are introduced as molecularly defined, single-component vectors in which reversible photoswitching controls plasmid DNA (pDNA) condensation pathways, dendriplex topology, and transfection behavior. The amphiphiles combine asymmetrically substituted azobenzene cores with ionizable and lipophilic dendrons and undergo efficient, reversible E/Z photoisomerization under biologically relevant conditions. In the presence of pDNA, they form nanocomplexes displaying markedly different supramolecular organizations depending on the architecture of the ionizable domain, ranging from highly ordered lamellar nanoparticles to morula-like or weakly structured condensates. Molecular mechanics and molecular dynamics simulations reveal that photoisomerization within preassembled lamellar dendriplexes introduces local structural frustration, transiently destabilizes bilayer organization, and enhances amphiphile dissociation. These structural perturbations correlate with enhanced intracellular delivery and transgene expression upon E ↔ Z interconversion. In vitro, Z-derived nanocomplexes systematically outperform the corresponding E-isomers in COS-7, HepG2, and RAW264.7 cells, while ex vivo photoswitching yields up to 50-fold increases in expression. In vivo studies further demonstrate isomer-dependent passive organ targeting, including pronounced shifts from lung- to liver-dominant transfection profiles. Collectively, these results establish molecular photoswitching as a mechanism to encode supramolecular DNA organization and biological function in single-component dendritic vectors.