Breast Cancer Bone Metastasis Therapy and Tumor‐Associated Bone Destruction Repair by Versatile Semiconducting Nanointegrators with X‐Ray Adjuvant

Abstract Tumor progress and tumor‐associated osteolysis are two key issues of breast cancer bone metastasis, which makes it challenging for bone metastasis treatment. To settle these two issues concurrently, a versatile semiconducting nanointegrator (termed as SPN CpG/Ca ) containing semiconducting polymer nanoparticle (SPN), Ca 2+ and cytosine‐phosphate‐guanine (CpG) oligonucleotides conjugated on the surface via a singlet oxygen ( 1 O 2 )‐responsive linker, is designed. The antitumor effect can be triggered with X‐ray irradiation as an adjuvant, in which SPN works as a radiosensitizer to produce 1 O 2 for radiotherapy and controlled release of CpG via disrupting 1 O 2 ‐responsive linkers. The Ca 2+ accumulation via SPN CpG/Ca delivering causes tumor cell death and the released CpG activates immune response to realize immunotherapy. The combinational action of radiotherapy, Ca 2+ overloading, and immunotherapy results in complete clearance of metastatic tumor cells in 4T1 breast cancer‐based bone metastasis mouse models. Furthermore, Ca 2+ can accelerate osteogenesis of bone marrow mesenchymal stem cells while CpG inhibits osteoclast differentiation in the bone metastasis microenvironment to alleviate osteolysis, which synergistically contributes to repair of tumor‐associated bone destruction. SPN CpG/Ca represents a versatile therapeutic nanosystem with the abilities to treat bone metastasis and repair tumor‐associated bone destruction, providing a new tactic for bone metastasis therapy.