Bone metastasis (BM) is a solid tumor confined to narrow bone marrow cavities with a relatively poor blood supply and hypoxic environment, making conventional anticancer treatments difficult. In our study, we fabricated nanoparticles (NPs) based on zeolitic imidazolate framework-8 (ZIF-8) loaded with indocyanine green (ICG, a photodynamic agent) and cytochrome c (Cyt c, an anticancer protein) with a surface modified by zoledronate (ZOL, a bone-targeting moiety) and a polyvinyl pyrrolidone (PVP) coating to increase their stability. The ICG/Cyt c@ZZF-8 NPs were expected to have synergistic antitumor therapy and bone protection efficiency. The in vitro and in vivo experiments showed the bone-targeted and pH-sensitive ability of ICG/Cyt c@ZZF-8 NPs, which could be engulfed by tumor cells and release the cargos. Upon 780 nm laser irradiation, ICG produces cytotoxic reactive oxygen species (ROS, 1O2) that directly kill tumor cells, and Cyt c with catalase-like activity can induce programmed cell death and decompose H2O2 to O2, thus enhancing the PDT efficiency. The ZOL can further inhibit bone resorption. The ICG/Cyt c@ZZF-8 NPs showed improved antitumor and bone protection efficiency in a mouse model of BM. This study demonstrated a potential mode for the synergetic therapy of orthopedic diseases.