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.