Photosensitizer and Chemotherapy Drug-Based Self-Assembled Nanoparticles for Ferroptosis-Mediated Therapy of Triple Negative Breast Cancer

Photodynamic therapy (PDT) is widely used for the treatment of triple-negative breast cancer (TNBC). Ferroptosis, characterized by the accumulation of reactive oxygen species (ROS) and lipid peroxidation (LPO), offers a promising therapeutic pathway. However, the overexpression of glutathione (GSH) and insufficient ROS at the tumor site often result in suboptimal therapeutic efficacy. In this study, we developed a carrier-free, tumor-targeting nanodelivery system known as Ce6-SS/celastrol nanoparticles (CSCN). It was self-assembled from disulfide-bonded photosensitizer, Ce6-SS, and natural active product celastrol (Cel). The particle size of CSCN was 127.5 nm. The disulfide bonds in CSCN can significantly reduce GSH levels in tumor cells, thereby preventing ROS scavenged by GSH and inhibiting glutathione peroxidase 4 (GPX4) production. Furthermore, Cel covalently binds to heme oxygenase-1 (HO-1) proteins, leading to LPO accumulation and induction of ferroptosis. Simultaneously, the significant elevation of ROS induced by both the disulfide bonds and Cel enhances the PDT effect of Ce6. This multifaceted synergistic nanoparticle system enhances PDT therapeutic effects, induces tumor cell ferroptosis, and exhibits significant antitumor activity in both in vitro and in vivo. These findings collectively demonstrated that CSCN enhanced anticancer effects and induced ferroptosis through the synergistic effect of PDT and chemotherapy. This multifaceted synergistic therapeutic strategy suggests that CSCN holds great potential for treating TNBC upon light exposure.