Tumor microenvironment-responsive micelles for mitochondrial copper depletion to enhance photodynamic therapy

Triple-negative breast cancer (TNBC) exhibits aberrant copper accumulation that promotes tumor progression and metastasis. Targeting copper homeostasis, particularly at the mitochondrial level, represents a promising yet underexplored therapeutic strategy. Herein, a mitochondria-targeted nano-micellar system Ce6-TPP@PSC was rationally engineered to achieve copper chelation-mediated amplification of PDT. The nano-micelles exhibited a uniform spherical morphology with an average diameter of 200 nm. Spectroscopic analyses indicated effective copper-binding capability, while electron spin resonance demonstrated that copper chelation did not compromise reactive oxygen species (ROS) generation under irradiation. At the cellular level, Ce6-TPP@PSC reduced intracellular copper levels and achieved efficient mitochondrial localization. This mitochondria-confined copper chelation sensitized tumor cells to oxidative stress, thereby amplifying ROS generation upon light irradiation and subsequently inducing immunogenic cell death. In an orthotopic TNBC model, this amplified PDT effect resulted in significant inhibition of tumor growth and metastasis. Ce6-TPP@PSC prolonged survival, with a 100% survival during the observation period. No evident tumor recurrence and metastasis were observed in treated mice within the experimental timeframe, whereas pronounced lung metastasis occurred in the control group. These findings demonstrate that copper chelation-mediated sensitization of PDT within a mitochondria-targeted nano-platform provides an effective strategy for suppressing TNBC progression and metastasis.