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. Schematic illustration of the preparation of IR780 and Erianin coloaded liposome (IR-E@Lip) and its therapeutic action against breast cancer. (I) Preparation of IR-E@Lip and its pH-responsive charge reversal within the acidic tumor microenvironment. (II) Positively charged IR-E@Lip markedly promotes endocytosis in tumor cells. After internalization, the mitochondrial-targeting property of IR780 enables both photodynamic therapy (PDT) and photothermal therapy (PTT), leading to immunogenic cell death (ICD). Simultaneously, the release of Erianin suppresses programmed cell death ligand 1 (PD-L1) expression, thereby enhancing antitumor immune responses in a synergistic manner. ATP: adenosine triphosphate; CRT: calreticulin; HMGB1: high-mobility group box 1; ROS: reactive oxygen species. • pH-responsive charge-reversal liposome enables prolonged circulation and tumor-targeted delivery. • Mitochondrial-targeted Photothermal Therapy (PTT) / Chemodynamic Therapy (CDT) potentiates immunogenic cell death. • This liposomal system enables a synergistic combination therapy integrating PTT , Photodynamic Therapy (PDT) , and chemotherapy.