A Cascade Drug DeliveryNanosystem for SynergisticTumor Suppression and Bone Resorption Inhibition in Breast CancerBone Metastasis

Abstract Bone metastasis is a major cause of mortality in patients with advanced breast cancer, and its treatment remains highly challenging because of the complex pathological microenvironment in bone tissue. Herein, we developed a dual-targeting nanoplatform for the cascade delivery of bisphosphonates and antitumor agents to synergistically treat breast cancer bone metastasis. Following systemic administration, zoledronic acid (ZOL)-functionalized nanoparticles Cu/ZIF@DL/SSZ-ZOL exhibit specific accumulation at bone metastasis sites, achieving drug delivery on the tissue level. Charge reversal of Cu/ZIF@DL/SSZ at the bone resorption interface leads to the detachment of ZOL and enhances the affinity of Cu/ZIF@DL/SSZ toward tumor cells, achieving drug delivery at the cellular level. After internalization by tumor cells, Cu/ZIF@DL/SSZ effectively suppress tumor cell proliferation via apoptosis, ferroptosis, and cuproptosis. The combined effects of ZOL-mediated inhibition of bone resorption and the Cu/ZIF@DL/SSZ-induced tumor inhibition effect disrupt the vicious cycle between tumor progression and bone destruction, resulting in potent antitumor efficacy. Consequently, this dual-targeting theranostic nanoagent achieves an effective treatment of breast cancer bone metastasis in animal models. Overall, this dual-targeting theranostic nanoagent offers a promising therapeutic strategy for the treatment of breast cancer bone metastases.