Peptide-based nanoassembly enhances ferroptosis in cancer to overcome paclitaxel resistance

Abstract

The development of chemotherapy resistance poses a major challenge in cancer therapy. Ferroptosis, a unique type of cell death, offers a promising strategy to combat this resistance. Herein, a peptide-based nanoassembly (PTX@CPG) consisting of paclitaxel (PTX), chlorin e6 (Ce6), and FFVLKPLGLAGK-(PEG8)₃ was constructed to promote ferroptosis through reactive oxygen species (ROS) accumulation and overcome chemoresistance. Specifically, the small-sized PTX@CPG nanoparticles effectively penetrate tumors, where the microenvironment-responsive peptide is selectively cleaved by the high expression of matrix metalloproteinase 2. This process facilitates the targeted release of PTX and its reassembly into nanofibers, improving the tumor retention of Ce6 and enhancing its cellular uptake. The synergistic therapeutic effects of PTX in combination with photodynamic therapy on triple-negative breast cancer cells were validated through both in vitro and in vivo experiments. Impressively, upon laser irradiation, PTX@CPG significantly increased ROS production, thereby amplifying the ferroptosis-inducing effects of PTX. Moreover, ferroptosis triggered by PTX@CPG with laser reduced the levels of P-glycoprotein and glutathione peroxidase 4, contributing to the alleviation of chemoresistance. Overall, PTX@CPG with laser demonstrated effective spatial targeting and drug retention, enhancing ferroptosis through ROS accumulation and showcasing a promising approach for overcoming chemotherapy resistance in cancer therapy.