Red light-mediated stepwise nitric oxide release via tandem photocatalysis for tumor therapy

The development of nitric oxide (NO) delivery systems with spatiotemporally controlled release is critical for achieving on-demand therapeutic effects while minimizing side effects. Although precise modulation of NO-release kinetics is highly desirable in biomedical applications, the design of single-component donors capable of controlled, stepwise release remains a significant challenge. Here, we report the first example of red-light-mediated, stepwise NO release from a single-component donor, enabled by a PdTPTBP photocatalyst via a photocatalytic mechanism. These donors were rationally constructed by covalently linking N-nitrosamine and N-nitrosamide moieties through an alkyl linker. While the N-nitrosamide moiety alone is unresponsive to red light, even in the presence of PdTPTBP, photocatalysis triggers rapid NO release (k ₁) from the N-nitrosamine group, generating a 4-nitroaniline intermediate. This intermediate then serves as an electron mediator, facilitating the subsequent activation of the N-nitrosamide moiety and inducing a slower secondary NO release (k ₂). Importantly, the release rate ratio (k ₁/k ₂) can be tuned from approximately 14 to 53.8 by varying the electron-withdrawing substituents on the 4-nitroaniline unit. Moreover, this photocatalytic NO delivery platform exhibits potent antitumor activity in both cultured tumor cells and tumor-bearing mice, highlighting the therapeutic advantage of localized, stepwise NO release.