Intracellular Co-Delivery of Carbon Monoxide and Nitric Oxide Induces Mitochondrial Apoptosis for Cancer Therapy

Understanding the interplay between gasotransmitters is essential for unlocking their therapeutic potential. However, achieving spatiotemporally controlled co-delivery to target cells remains a significant challenge. Herein, we propose an innovative strategy for the intracellular co-delivery of carbon monoxide (CO) and nitric oxide (NO) gasotransmitters under clinically relevant wavelengths. This approach rationally couples aerobic photooxidative and anaerobic photocatalytic reactions within a polymeric micelle platform, using palladium(II) tetraphenyltetrabenzoporphyrin (PdTPTBP) as both photosensitizer and photocatalyst. Notably, the photooxidation-mediated release of CO generates a local hypoxic microenvironment, which facilitates the photoredox catalyzed release of NO. This self-adaptive micelle platform enables efficient uptake by tumor cells and intracellular co-delivery of CO and NO under 630 nm light irradiation, demonstrating potent anti-tumor activity in a 4T1 tumor-bearing mouse model via the synergistic induction of mitochondrial apoptosis.