Tumor acid-triggered sericin prodrug colloidal system for enhanced photodynamic and ferroptosis therapy of breast cancer.

Image-guided tumor therapy is an integrated approach for visualized and targeted delivery, which synchronizes diagnosis and treatment to achieve complete tumor eradication. Reactive oxygen species (ROS) show promise for cancer therapy by provoking neoplastic oxidative damage; however, their therapeutic efficacy is substantially constrained by the intracellular antioxidant defense system. Inhibiting solute carrier family 7 member 11 (SLC7A11, also known as xCT) has been demonstrated to downregulate intracellular glutathione (GSH) levels, thereby not only enhancing oxidative stress but also triggering ferroptosis, a recently identified form of programmed cell death. Here, we proposed a multi-faceted ROS amplification strategy to induce tumor oxidative damage by constructing cinnamaldehyde (CA)- and ROS-producing purpurin 18 (P18)-conjugated sericin prodrug (SNCPS) encapsulated with xCT inhibitor sulfasalazine (SAS). It was confirmed that the ROS-induced oxidative damage by 660 nm laser-assisted SNCPS was multilaterally amplified by virtue of the down-regulation of SAS-based anti-oxidative stress responses in tumor cells, ultimately leading to highly efficient photodynamic and ferroptosis effects. Furthermore, the near-infrared fluorescence properties of the fluorescent molecule P18 were exploited for in vivo imaging to track the distribution of its nano-formulation. In vivo assays showcased the strong antitumor potency of SNCPS in 4T1 tumor-bearing mice, with no apparent systemic toxicity observed. This work presents a highly promising strategy for designing antitumor agents via the multilateral amplification of oxidative stress.