The electronic, optical,
and redox properties of thiophene-based
materials have made them pivotal in nanoscience and nanotechnology.
However, the exploitation of oligothiophenes in photodynamic therapy
is hindered by their intrinsic hydrophobicity that lowers their biocompatibility
and availability in water environments. Here, we developed human serum
albumin (HSA)–oligothiophene bioconjugates that afford the
use of insoluble oligothiophenes in physiological environments. UV–vis
and electrophoresis proved the conjugation of the oligothiophene sensitizers
to the protein. The bioconjugate is water-soluble and biocompatible,
does not have any “dark toxicity”, and preserves HSA
in the physiological monomeric form, as confirmed by dynamic light
scattering and circular dichroism measurements. In contrast, upon
irradiation with ultralow light doses, the bioconjugate efficiently
produces reactive oxygen species (ROS) and leads to the complete eradication
of cancer cells. Real-time monitoring of the photokilling activity
of the HSA–oligothiophene bioconjugate shows that living cells
“explode” upon irradiation. Photodependent and dose-dependent
apoptosis is one of the primary mechanisms of cell death activated
by bioconjugate irradiation. The bioconjugate is a novel theranostic
platform able to generate ROS intracellularly and provide imaging
through the fluorescence of the oligothiophene. It is also a real-time
self-reporting system able to monitor the apoptotic process. The induced
phototoxicity is strongly confined to the irradiated region, showing
localized killing of cancer cells by precise light activation of the
bioconjugate.