Biomimetic Self-Assembled Chlorin e6/Capsaicin nanoparticles for Hypoxia-Alleviated photodynamic therapy of Triple-Negative breast cancer

The hypoxic tumor microenvironment is an important barrier restricting the therapeutic efficacy of photodynamic therapy (PDT) for triple-negative breast cancer (TNBC), while adaptive antioxidant defense may further compromise ROS-mediated damage. Therefore, alleviating tumor hypoxia has emerged as a practical strategy to enhance the anti-tumor potency of PDT, and modulation of antioxidant defense provides an additional sensitizing effect. Based on the unique roles of capsaicin (Cap) in regulating the above two aspects, this study constructed a biomimetic nanodelivery system for enhanced photodynamic therapy (M1@Ce6/Cap NPs). Cellular experimental results showed that the system alleviated cellular hypoxia and downregulated Nrf2 expression, a key transcription factor in the oxidative stress defense pathway, thereby contributing to enhanced Ce6-mediated PDT. Further experiments using TNBC tumor-bearing mouse models supported the enhanced therapeutic effect, with 1.48-fold higher tumor accumulation, 1.59-fold greater intratumoral penetration, and a tumor inhibition rate of 70.6 % after laser irradiation. These findings provide experimental support for a biomimetic strategy that integrates hypoxia alleviation with additional antioxidant defense modulation to enhance PDT against TNBC.