Iridium(III)-based luminescent biosensors for cancer biomarker detection: From molecular design to clinical translation.

Cyclometalated iridium (III) [Ir(III)] complexes are a new generation of octahedral d6 transition metal-based emissive species that exhibit characteristics that overcome important analytical constraints that are present within existing clinical oncology immunoassay systems. This review evaluates Ir(III) luminescent biosensors for the detection of cancer biomarkers, considering their applications in clinical chemistry and diagnostic laboratory medicine. The d6 electronic configuration of iridium facilitates efficient spin-orbit coupled intersystem crossing to the low-lying triplet metal-to-ligand charge transfer excited states. Consequently, this property can be utilized to suppress autofluorescence in time-gated detection formats. The ligand system can be modified systematically and the emission wavelengths (450-800 nm) can be adjusted to avoid spectral overlaps with hemoglobin absorption interference in blood-based samples. In complex biological matrices, with co-reactant mediated electrode reaction, ECL signals are generated without any external photoexcited species to induce background signal, which significantly reduces background signal. Tumor markers in serum, circulating nucleic acids, and exosomal biomarkers at attomol/L and fmol/L concentrations can be detected using MOF/COF scaffold-doped luminophores, self-enhanced intramolecular ECL reagents, and nanomaterial-amplified detection cascades. Translation barriers, such as endogenous matrix interference, manufacturing reproducibility, cytotoxicity and biocompatibility of Ir(III) complexes, compliance with ISO 15189, and IVD regulatory considerations through the FDA and European IVDR 2017/746 frameworks, are highly evaluated. It critically evaluates the reported analytical performance against established clinical immunoassay benchmarks (e.g., Roche Elecsys, Abbott Architect) based on the CLSI validation and ISO metrology standards. Additionally, it outlines a translational roadmap with defined technological readiness milestones for implementing these biosensors in clinical laboratories, particularly in precision oncology.