Activatable companion theranostics for dual-modality imaging-escorted pyroptosis-propelled synergistic cancer therapy

Companion diagnostics (CDx) plays a pivotal role in precision medicine for cancer treatment. However, conventional CDx are often limited by their inability to provide real-time monitoring of cancer progression and therapeutic responses. Herein, we develop a dual-modality imaging-based companion theranostic (CTx) nanoplatform (LET-Cl@GOx), which integrates activatable photoacoustic (PA) and fluorescence (FL) imaging to enable the enhanced diagnostic accuracy and real-time therapeutic feedback, while demonstrating cascade-amplified photothermal/starvation synergistic therapy. The LET-Cl@GOx is designed by the assembly of glucose oxidase (GOx) with a pH-activatable near-infrared (NIR) dye (LET-Cl), enabling the turn-on of PA/FL imaging within the acidic tumor microenvironment (TME). The dynamic alterations of PA/FL imaging signals provide real-time feedback on TME acidification, enabling accurate monitoring of GOx catalysis progression and precision timing of photothermal therapy (PTT) intervention. Furthermore, the GOx-mediated tumor starvation reduces adenosine triphosphate (ATP) levels, leading to the diminished heat shock protein expression and consequently enhanced the sensitivity to PTT. Concurrently, the photothermal effect reciprocally enhances the catalytic activity of GOx, establishing a triple closed-loop system with positive feedback amplification. This multiscale-augmented synergistic therapy triggers robust pyroptosis via the Caspase-3/gasdermin E signaling pathway, demonstrating remarkable therapeutic efficacy of tumors <i>in vivo</i>.