Intervention with the Bone-Associated Tumor Vicious Cycle through Dual-Protein Therapeutics for Treatment of Skeletal-Related Events and Bone Metastases.

Bone metastasis is a common metastasis site such as lung cancer, prostate cancer, and other malignant tumors. The occurrence of bone metastases of lung cancer is often accompanied by bone loss, fracture, and other skeletal-related events (SREs) caused by tumor proliferation and osteoclast activation. Furthermore, along with the differentiation and maturation of osteoclasts in the bone microenvironment, it will further promote the occurrence and development of bone metastasis. Protein drugs are one of the most promising therapeutic pharmaceuticals, but in vivo delivery of protein therapeutics still confronts great challenges. In order to more effectively conquer bone metastases and alleviate SREs, herein, we constructed biomineralized metal-organic framework (MOF) nanoparticles carrying protein toxins with both bone-seeking and CD44-receptor-targeting abilities. More importantly, through combination with Receptor Activator of Nuclear Factor-κ B Ligand (RANKL) antibody, in vivo results demonstrated that these two protein agents not only enhanced the detraction effects of protein toxin agents as ribosome-inactivating protein (RIP) on bone metastatic tumor cells but also exhibited synergistic intervention of the crosstalk between bone cells and tumor cells and reduced SREs such as bone loss. Collectively, we expect that this strategy can provide an effective and safe option in regulating bone-tumor microenvironments to overcome bone metastasis and SREs.