Programmed Design of Nitric Oxide and Photodynamic Therapy Based on Orthogonal Upconversion Nanoparticles Improves Anti‐Tumor Efficacy via Protein S‐nitrosylation

The effectiveness of cancer treatment has been significantly improved through combined therapies that synergistically utilize multiple treatment modalities. While combination strategy mitigates tumor resistance, enhances therapeutic efficacy, and reduces side effects compared to monotherapies, the precise coordination of treatment sequences and timing remains underexplored, particularly in the nanomaterial-based therapies. In this study, this gap is addressed by investigating the interaction between photodynamic therapy (PDT) and nitric oxide (NO) therapy, with a specific focus on the sequence in which these therapies are administered. An upconversion nanoplatform is designed with orthogonal dual-channel fluorescence properties, allowing for non-interfering NO release and PDT, which enables systematic exploration of the effects of treatment sequence on therapy efficacy. The results demonstrate that administering NO therapy prior to PDT yields superior antitumor effects compared to other sequences. This time-sequenced efficacy may be attributed to NO-induced S-nitrosylation, which disrupts the intracellular regeneration cycle of reduced glutathione, thereby sensitizing tumor cells to subsequent PDT.