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.

High invasion and metastasis are the major obstacles to successful breast cancertherapy. Indocyanine green (ICG), a photosensitizer for photothermal therapy (PTT), shows potent anticancer efficacy when combined with the chemotherapeutic drug doxorubicin (DOX). Human serum albumin (HSA), a biocompatible carrier material, has been successfully used for the delivery of paclitaxel (Abraxane). In addition, there are ICG functional binding regions in HSA. Thus, a smart assembled nanoplatform (DI@HSA NPs) was constructed to achieve the synergistic effects of chemo- photothermal therapy against breast cancer. Compared to free ICG and free DOX, DI@HSA NPs showed satisfactory stability and exhibited an enhanced tumor targeting capacity. The mild hyperthermia generated by DI@HSA NPs can not only cause tumor photothermal ablation and promote the uptake of DI@HSA NPs by 4T1 cells, but also protect the healthy tissues nearby the tumor from overheating injury. More importantly, DI@HSA NPs greatly amplified the infiltration of CD4+ T cells and CD8+ T cells, resulting in inhibited tumor growth and metastasis. DI@HSA NPs, as a simple biocompatible nanoagent, showed excellent inhibition of breast cancer growth and metastasis by chemo-photothermal therapy, providing a potential strategy for the future therapy of breast cancer.