Charge-reversal biodegradable nanoplatform with ferroptosis and ICD induction for tumor synergistic treatment

Ferroptosis is a form of regulated cell death (RCD) induced by excessive lipid peroxidation, representing a promising mechanism for suppressing tumors. Herein, a type of nanoplatform (ODLP-PEGH8) was developed to harness the power of ferroptosis and immunogenic cell death (ICD) for the treatment of breast cancer. To enhance its effectiveness, this project incorporated a pH-responsive PEGH8 peptide onto the surface of the nanoplatform. This modification not only promoted charge reversal within the tumor microenvironment but also improved the cellular uptake efficiency of the nano-system, facilitating intracellular lysosomal escape. Subsequently, ODLP-PEGH8 rapidly degraded under conditions of low pH and exposure to light, resulting in the sequential release of the ferroptosis inducer lapatinib (LTB) and oxaliplatin (OXA). LTB induced ferroptosis and exhibited potent tumor cell-killing effects, while the ODLP-PEGH8, which possessed photothermal properties, worked with OXA to effectively induce ICD within the tumor. This dual approach triggered anti-tumor immune responses and had a substantial impact on tumor immunotherapy. All the results confirm that ODLP-PEGH8 mediates ferroptosis, enhancing the proliferation and infiltration of cytotoxic lymphocytes (CLTs) while demonstrating excellent biological safety in vivo. These findings suggest a promising therapeutic strategy for targeting ferroptosis in cancer treatment.