Medicine treatments for bone-related diseases such as osteoporosis, bone metastasis, osteomyelitis, and osteolysis are often limited by insufficient drug concentration at the lesion sites owing to the low perfusion of bone tissue. A carrier that can deliver multiple bone destruction site-targeting drugs is required to address this limitation. Here, we reported a novel bone-targeting nano-drug delivery platform formed by the integration of zoledronate (ZOL) and zeolitic imidazolate framework-8 (ZIF-8) nanoparticles. The ZOL mixed zeolitic imidazolate framework (ZZF) nanoparticles were synthesized in water at room temperature (25 °C), where many biomacromolecules could maintain their activity. This allowed the ZZF nanoparticles to adapt the encapsulation ability and pH response release property from ZIF-8 and the excellent bone targeting performance of ZOL simultaneously. Considering the ease of preparation and biomacromolecule-friendly drug delivery of this nano platform, it may be useful in treating bone-related diseases.