Severe injuries and diseases of bone tissue caused by congenital disorder, extrinsic trauma, infection, and osteosarcoma resection face significant challenges for complete recovery. The current treatment options with therapeutic molecules (e.g., drugs, proteins, genetic molecules) often involve vector-borne infection, restrictive availability, donor deficiency, and immune rejection, whereas the materials-based nanotherapeutics can tackle these issues. Nanotherapeutics can secure the stability and activity of cargo molecules, allow their controlled release, and even target the specific cells and organelles, all of which eventually improve the in vivo efficacy while relieving the off-target concerns. Here we systematically review the recent progress in materials-based nanotherapeutics for the treatment of injured and diseased bone, highlighting the processing nanotechnologies and delivery strategies of various classes of therapeutic molecules that intervene specific cells and intracellular signaling pathways. Nanotherapeutics combined with three-dimensional matrices are also underscored that can recruit endogenous cells and sequester intrinsic therapeutic molecules, ultimately supporting and boosting the microenvironment for regenerative process. Future aspects in the development of nanotherapeutics approach and clinical availability are also discussed.