CuPc-Fe@BSA nanocomposite: Intracellular acid-sensitive aggregation for enhanced sonodynamic and chemo-therapy

Due to their rigid π-conjugated macrocyclic structure, organic sonosensitizers face significant aggregation in physiological conditions, hindering the production of reactive oxygen species (ROS). An acid-sensitive nanoassembly was developed to address this issue and enhance sonodynamic therapy (SDT) and emission. Initially, copper phthalocyanine (CuPc) was activated using a H 2 SO 4 -assisted hydrothermal method to introduce multiple functional groups (–COOH, –OH, and −SO 3 H), disrupting strong π–π stacking and promoting ROS generation and emission. Subsequently, negatively charged CuPc-SO 4 was incorporated into bovine serum albumin (BSA) to form CuPc-Fe@BSA nanoparticles (10 nm) with Fe 3+ ions serving as linkers. In acidic conditions, protonation of CuPc-SO 4 and BSA weakened the interactions, leading to Fe 3+ release and nanostructure dissociation. Protonated CuPc-SO 4 tended to self-aggregate into nanorods. This acidity-sensitive aggregation is vital for achieving specific accumulation within the tumor microenvironment (TME), thereby enhancing retention and SDT efficacy. Prior to this, the nanocomposites demonstrated cycling stability under neutral conditions. Additionally, the released Fe ions exhibited mimicry of glutathione peroxidase and peroxidase activity for chemotherapy (CDT). The synergistic effect of SDT and CDT increased intracellular oxidative stress, causing mitochondrial injury and ferroptosis. Furthermore, the combined therapy induced immunogenic cell death (ICD), effectively activating anticancer immune responses and suppressing metastasis and recurrence.