Nitric oxide (NO) is an inorganic free radical that plays a multifaceted role in regulating numerous physiological and pathophysiological processes and is gaining increasing recognition as a powerful unconventional therapeutic agent for the treatment of severe diseases, including cancer. However, its high reactivity and the need for precise control over its site- and time-specific release pose significant challenges for clinical translation. Light-triggered delivery of NO from suitable photoprecursors represents a compelling strategy to address these challenges, especially if its delivery times are compatible with therapeutic windows.

Here, we present a conceptually novel supramolecular approach for the catalytic photoactivation of a blue light-responsive NO photodonor (NOPD) using biocompatible red light, which is made possible by photosensitized energy transfer within nanocarriers. This strategy achieves a remarkable red-shift of approximately 300 nm, enabling activation at longer, clinically relevant wavelengths.

By co-encapsulating red light-absorbing photosensitizers (PSs) and the NOPD into various biocompatible nanocarriers, we establish a new photoreactive environment where the PS triplet state initiates NO release through an oxygen-competitive pathway. This ensures effective release under both aerobic and anaerobic conditions, broadening potential biological applications.

Notably, the process also yields a fluorescent photoproduct, offering a built-in optical reporter for real-time monitoring of NO generation. This integrated activation/reporting mechanism, achieved without chemical modification of the NOPD or the use of complex light sources, introduces a versatile and scalable platform for NO-based phototherapies. This work offers a transformative advance in light-mediated NO delivery by uniting supramolecular photochemistry, nanotechnology, and clinical biocompatibility, opening up new avenues for minimally invasive therapeutic strategies.