Although widely used in clinical diagnostics, the sensitivity of electrochemiluminescence (ECL) bead-based immunoassays is intrinsically limited by the reaction mechanism driving the emission of [Ru(bpy)3]2+ on the bead surface. Depending mostly on the coreactant oxidation, the ‘remote’ pathway is hindered by the slow coreactant oxidation rate and the short half-lives of electrogenerated radicals. In this work, we synthesized a [Ru(bpy)3]2+ derivative featuring a stimuli-responsive disulfide bond in its linker to the bead. Electrogenerated tri-n-propylamine (TPrA) neutral radicals reduce disulfide moieties, electrochemically inducing the release of Ru(II) labels in solution and thereby leading to an unprecedented mechanism shift toward the more efficient “homogeneous” ECL pathway. Leveraging ICP-MS, ECL microscopy, and finite element simulations, we demonstrate rapid bond cleavage and an impressive signal enhancement of up to 613%. Using an experimental configuration designed to emulate commercial clinical analysis, we developed an ECL-based immunoassay for the rapid detection of the SARS-CoV-2 Spike (S) protein in whole virus samples from swab formulations. The immunosensor incorporating the cleavable luminophore demonstrated a 40% lower detection limit and a 2-fold increase in sensitivity, while reducing TPrA consumption by 72%. These findings establish stimuli-responsive luminophores as a groundbreaking class of ECL labels, promising substantial improvements in the sensitivity of commercial biosensors.