Nanogenerators with l-arginine loading: new choices as cascade and synergistic nitric oxide/photodynamic antitumor agents

Photodynamic therapy (PDT) is widely used in tumor treatment because it has few side effects and good therapeutic specificity. However, its therapeutic effect is severely limited by the insufficient oxygen supply and high glutathione (GSH) concentration in the tumor environment. Recently, nitric oxide (NO) has been widely used as a physiological regulatory factor and tumor inhibitor in various pathological processes. NO can kill tumor cells by reacting with O₂˙⁻ to produce highly lethal ONOO⁻. Importantly, NO can promote vasodilation to improve hypoxia in the tumor environment and interfere with the antioxidant defense of GSH, improve the sensitivity of the tumor to ROS, and enhance the effect of PDT. However, since NO has a very short half-life and is gaseous, it cannot be used directly in the clinic. As a rule, the use of NO donors is required. L-Arginine (L-Arg) is a natural NO donor that can produce NO under the action of ROS, so that effective synergy of NO/PDT can be achieved by combining L-Arg and a photosensitizer. On this basis, cascade and synergistic NO/PDT antitumor therapy with L-Arg has been reported in recent years. However, a relevant review on cascade and synergistic NO/PDT based on the combination of L-Arg and photosensitizers has not been published. Therefore, in this review, we summarize the recent advances in synergistic NO/PDT for antitumor therapy based on the interaction of L-Arg and various photosensitizers in the last five years. The design idea, synergistic mechanism and application prospects of the two treatment methods are explained in detail. The remaining challenges and future opportunities in this field are also highlighted. We believe that this review will provide a better understanding of cascade and synergistic NO/PDT through multifunctional nanomaterials and advance nanoscience and nanotechnology step by step towards clinical applications.