Augmented therapeutic efficacy of Erianin through pH-responsive charge-reversal liposome integrated synergistic PTT and PDT in breast cancer.

To address Erianin's limited solubility and the insufficient efficacy of single-modality chemotherapy, a charge-reversal liposomal system co-encapsulating Erianin and IR780 was designed. The liposomes maintain a negative surface charge under physiological conditions to prolong circulation, but undergo pH-responsive conversion to a positive charge within the acidic tumor microenvironment (pH 6.5-6.8), thereby improving tumor-selective internalization. The optimized formulation achieved targeted mitochondrial delivery, where IR780-induced reactive oxygen species (ROS) production and mild hyperthermia activated stress pathways, leading to mitochondrial disruption and ultimately initiating immunogenic cell death (ICD). Concurrently, encapsulated Erianin effectively suppressed photothermal therapy (PTT)/photodynamic therapy (PDT)-induced programmed cell death ligand 1 (PD-L1) upregulation. This nanoplatform not only avoids the drawbacks of conventional chemotherapy but also establishes a synergistic therapeutic framework integrating PTT, PDT, and chemotherapy. By counteracting resistance mechanisms and limiting immune checkpoint expression, the system provides robust antitumor activity and introduces an innovative approach for advancing liposomal strategies in combinatorial cancer therapy.