Beyond ROS: Red-Light Photocatalytic Liposomes for Hypoxia-Resistant Cancer Therapy

Objective

Light-activated strategies have transformed medicine, yet current approaches face major limitations. Photodynamic therapy (PDT) depends on oxygen to generate reactive oxygen species (ROS), restricting efficacy in hypoxic tumors. Photoactivated chemotherapy (PACT) releases active drugs upon irradiation but is non-catalytic, preventing sustained reactivity. A promising alternative is bioorthogonal photocatalysis, where light-driven catalysts perform specific, non-natural transformations catalytically in biological systems. Using porphyrins, widely implemented in PDT, we will repurpose them as photocatalysts for the first catalytic strategy to generate therapeutic alkyl radicals in situ, highly cytotoxic species already shown to be effective against cancer but so far limited to prodrugs requiring enzymatic cleavage. Because enzyme activity varies and is often low in tumors, this strategy lacks robustness. By contrast, red-light activated porphyrins can trigger radical formation independently of enzymes, offering a powerful, catlytic, oxygen-independent therapeutic pathway. Red-light-absorbing porphyrins are particularly suited for biological use, operating via single electron transfer (SET) under mild conditions and activating precursors such as Hantzsch esters and Katritzky salts, already validated for their biocompatibility. To overcome solubility and stability challenges, we will pioneer RedLips: red-light-activated photocatalytic liposomes. Liposomes, clinically proven nanocarriers, can encapsulate or embed porphyrins while maintaining catalytic activity, enabling radical formation directly in aqueous and cellular environments. RedLips thus represent the first catalytic nanoplatform designed to produce alkyl radicals beyond ROS in situ, with spatial and temporal control. This project pioneers a new therapeutic paradigm: catalytic, oxygen-independent radical nanotherapy, pushing light-driven cancer treatment beyond the current state of the art.