A Microenvironment-Driven Peptide Nanoplatform Enhances Ferroptosis and Antiangiogenic Activity for Triple-Negative Breast Cancer Therapy

Triple-negative breast cancer (TNBC) remains a major clinical challenge due to its aggressive nature and limited therapeutic options. Among emerging therapeutic approaches, ferroptosis induction has attracted increasing attention due to its unique mode of action; however, its efficacy is often restricted by insufficient intratumoral drug accumulation and the abnormal tumor vascular microenvironment. Here, we designed a CREKA-modified peptide, Pep1, to actively target tumor-associated fibrin and increase accumulation in the tumor and further developed a pH-responsive self-assembling nanoplatform, PS/Pep1. PS/Pep1 significantly improved intratumoral drug bioavailability, promoted lipid peroxidation, suppressed glutathione peroxidase 4 (GPX4) activity, and downregulated vascular endothelial growth factor (VEGF) expression, thereby inducing ferroptosis- and apoptosis-mediated tumor cell death while suppressing angiogenesis. Upon exposure to the acidic tumor microenvironment, PS/Pep1 transformed from spherical nanoparticles into aggregates with high aspect ratios, facilitating deep tumor penetration and sustained local retention. In summary, this study presents a smart nanomedicine strategy that integrates active targeting, microenvironment-responsive structural transformation, and the synergistic regulation of ferroptosis-mediated cell death and angiogenesis, providing a promising therapeutic paradigm for TNBC treatment.