Carrier‐Free Stimulus‐Responsive Theranostic Nanoprodrug Enabling GSH‐Consumption‐Promoted Chemo‐Photodynamic Cancer Therapy

Synergistic chemo-photodynamic therapy has been proven more effective for cancer treatment compared to traditional chemotherapy and photodynamic therapy alone. Leveraging the characteristic of cancer cells that glutathione (GSH) plays an indispensable role in the development of drug resistance and reactive oxygen species (ROS) neutralization, we developed a carrier-free GSH-consuming theranostic nanoprodrug to deeply explore the GSH-consumption-promoted synergistic chemo-photodynamic therapy for boosted cancer treatment. The GSH-consuming nanoprodrug consists of paclitaxel (PTX) and a boron-dipyrromethene (BODIPY)-based photosensitizer, linked through a GSH-responsive self-immolating drug linkage; to serve as a control, a non-GSH-consuming nanoprodrug consisting of those two moieties linked by a non-biocleavable linkage was also developed. The carrier-free nanoprodrugs have a diameter of ∼65 nm and an ultrahigh drug loading content (>70%), and have exhibited highly efficient suppression against tumor proliferation upon light irradiation to trigger their photodynamic effect, more potent than the free PTX drug, because of the synergistic chemo-photodynamic therapy. Attractively, the GSH-consuming theranostic nanoprodrug, in comparison with its non-GSH-consuming counterpart, exerted extraordinarily powerful therapeutic effects, benefiting from its integrated advantages, including GSH-activated traceless PTX release, reduced drug resistance, and disabled ROS neutralization of cancer cells due to the consumption of intracellular GSH, resulting in the ultimate eradication of tumors.