Mitochondria-Targeting Type-I Photodrug: Harnessing Caspase-3 Activity for Pyroptotic Oncotherapy.

Precise control of cellular signaling events during programmed cell death is crucial yet challenging for cancer therapy. The modulation of signal transduction in cancer cells holds promise but is limited by the lack of efficient, biocompatible, and spatiotemporally controllable approaches. Here we report a photodynamic strategy that modulates both apoptotic and pyroptotic cell death by altering caspase-3 protein activity and the associated signaling crosstalk. This strategy employs a mitochondria-targeting, near-infrared activatable probe (termed M-TOP) that functions via a type-I photochemical mechanism. M-TOP is less dependent on oxygen and more effective in treating drug-resistant cancer cells, even under hypoxic conditions. Our study shows that higher doses of M-TOP induce pyroptotic cell death via the caspase-3/gasdermin-E pathway, whereas lower doses lead to apoptosis. This photodynamic method is effective across diverse gasdermin-E-expressing cancer cells. Moreover, the M-TOP mediated shift from apoptotic to pyroptotic modulation can evoke a controlled inflammatory response, leading to a robust yet balanced immune reaction. This effectively inhibits both distal tumor growth and postsurgical tumor recurrence. This work demonstrates the feasibility of modulating intracellular signaling through the rational design of photodynamic anticancer drugs.

Redox-Activatable and Acid-Enhanced Nanotheranostics for Second Near-Infrared Photoacoustic Tomography and Combined Photothermal Tumor Therapy.

Tumor phototheranostics in the second near-infrared window (NIR-II, 1000-1700 nm) holds great promise due to high spatiotemporal precision, enhanced penetration depth, and therapeutic efficacy. However, current "always-on" NIR-II phototheranostic agents remain restricted by the inherent nonspecificity from the pseudosignal readout and undesirable treatment-related side effects. To address these challenges, herein we explore an activatable and biocompatible nanotheranostics that generates diagnostic and therapeutic effects only after specific activation and enhancement by tumor microenvironmental redox and acid while keeping silent at normal tissues. Such an intelligent "turn-on" chromogenic nanotheranostics allows in vivo nearly zero-background photoacoustic tomography (PAT) and combined effective photothermal tumor therapy (PTT) both in the NIR-II range with minimal adverse effects. In light of the high sensitivity, superior penetration depth, and biocompatibility, this stimuli-activatable NIR-II photo-nanotheranostics provides broad prospects for the investigation and intervention of deep-tissue redox and acid-associated physiological and pathological events.