Water‐Responsive Hybrid Nanoparticles Codelivering ICG and DOX Effectively Treat Breast Cancer via Hyperthermia‐aided DOX Functionality and Drug Penetration

Abstract Tumor growth and metastasis are the major causes of high mortality in breast cancer. In this study, a water‐responsive phospholipid‐calcium‐carbonate hybrid nanoparticle (PL/ACC‐DOX&ICG) surface modified with a phospholipid shell is designed and covered with a shielding polymer polyethylene glycol; this development is loaded with the photosensitizer indocyanine green (ICG) and the chemotherapeutic drug doxorubicin (DOX) for near‐infrared (NIR) imaging and chemophotothermal combination therapy against breast cancer. PL/ACC‐DOX&ICG exhibits satisfactory stability against various aqueous environments with minimal drug leakage and can readily decompose to facilitate quick drug release into cancer cells. In vivo biodistribution studies, PL/ACC‐DOX&ICG demonstrated strong tumor‐homing properties. Interestingly, the in vitro cellular uptake and intratumoral penetration depth of PL/ACC‐DOX&ICG are significantly enhanced under NIR laser irradiation, owing to ICG‐induced hyperthermia, which not only enhances cell permeability and fluidity but also disrupts the dense tumor extracellular matrix. Compared to chemotherapy or photothermal therapy alone, chemophotothermal combination therapy synergistically induces apoptosis and death in 4T1 cells. Moreover, compared with the phosphate buffer saline group, the combined treatment suppress primary tumor growth at a rate of approximately 94.88% and decrease the number of metastatic nodules by about 93.6%. Therefore, PL/ACC‐DOX&ICG may be a promising nanoplatform for breast cancer treatment.