TPE-peptide@CaCO₃ targeting mitochondrial calcium overload and PDT synergistic tumor therapy

The high mortality rate of cancer necessitates the development of efficient treatments. Here, we developed acid-sensitive CaCO₃ (calcium carbonate) particles loaded with TPE (tetraphenylethylene)-peptide conjugates for mitochondrial targeted calcium overload, PDT (photodynamic therapy) and cancer therapy. TPE-peptide@CaCO₃ particles dissociate in a pH-dependent manner, allowing the rapid release of Ca²⁺ and TPE-peptide in the acidic tumor microenvironment. The positively charged peptide components have excellent water solubility, strong cell penetration, and precise mitochondrial targeting. Through imidazole group coordination and Ca²⁺ interaction, TPE-peptide probes self-assemble and activate AIE (aggregation-induced emission) for mitochondrial illumination. Meanwhile, the internalized TPE-peptide complex facilitated the mitochondrial delivery of exogenous Ca²⁺, resulting in massive Ca²⁺ accumulation and disruption of mitochondrial Ca²⁺ homeostasis. In addition, PDT by TPE-peptide@CaCO₃ can deplete local oxygen and increase the level of ROS (reactive oxygen species), amplifying mitochondrial Ca²⁺ overload through an ICD (immunogenic cell death)-related mechanism to achieve a good tumor therapeutic effect. The TPE-peptide@CaCO₃ system designed in this study can not only serve as a mitochondrial imaging guide and Ca²⁺ modulator targeting mitochondrial calcium overload, but also as a photodynamic agent and ICD inducer to play a role in synergistic anti-cancer therapy, providing new ideas for cancer treatment.