Zinc Assembled Gold Nanoclusters with Drug Conjugation for Theranostics and Intracellular Ratiometric Reporting

Abstract Nanotheranostic platforms incorporating multimodal functionalities have been explored for integrated diagnostic and drug delivery applications; however, in many systems, drugs are associated through supramolecular interactions, often leading to premature release and limited control over site-specific activation. In this work, a zinc-mediated assembly of Zn−Au nanoclusters (Zn−Au NCs) was developed, in which doxorubicin (DOX) was conjugated through zinc−amine coordination, as supported by FTIR spectroscopy and computational analysis. Density functional theory calculations revealed a short N···Zn coordination contact (2.10 Å), indicating strong metal−ligand anchoring of DOX, together with a stabilizing hydrogen-bond interaction, while a longer H···Au separation (3.88 Å) suggested a weak secondary interaction with the gold framework. Spectral overlap between DOX absorption and Zn−Au NC emission indicated energy transfer, corroborated by time-resolved photoluminescence and DFT studies. Geometry optimizations showed that zinc-mediated coordination enforced short donor−acceptor separations and induced interfacial charge redistribution, enhancing electronic coupling. Electrostatic potential and frontier orbital analyses revealed charge polarization and LUMO localization on DOX, consistent with interfacial charge-transfer character. Biologically, the combined formulation exhibited enhanced cytotoxic activity with a reduced IC50 value (0.17 μM). pH-responsive DOX release was achieved in serum and cellular environments, with monitoring enabled by dual-ratiometric fluorescence.