ABSTRACT The excitement about nanomedicine stems from the potential application of nanoscience to solve challenging medical problems. Inorganic nanoparticles (iNPs) exhibit unique properties that favor their diverse application in medicine, engineering, science, and technology. The large surface-to-volume ratio of these iNPs provides sites for the attachment of multiple drugs or imaging agents for therapy and imaging of diverse human diseases. Further conjugation of biological entities, such as proteins, nucleic acids, and lipids, confers specific targeting of these iNPs to desired tissues in vivo. Recent studies have shown that the intrinsic properties of some iNPs can be harnessed for therapeutic outcomes. Still, spontaneous stimulation of intrinsic therapeutic effects through interactions of the NPs with intracellular organelles, proteins, or molecular processes is difficult to control, leading to significant off-target toxicity. An alternative therapeutic approach is to transform some iNPs into nanoscale energy transducers. Quantum dots, upconversion NPs, carbon nanomaterials, and photocatalytic NPs are some nanoscale energy transducers that have shown promise in the treatment of human diseases. The excellent redox properties of these nanophotosensitizers offer high spatiotemporal control and precision phototherapy upon absorption of light. Two major limitations of current phototherapeutic interventions are the limited penetration of light used to activate the photosensitizers, which confines therapy to shallow lesions, and the frequent reliance on molecular oxygen to generate cytotoxic reactive oxygen species, a condition that precludes the effective treatment under the hypoxic conditions found in many solid and hematologic tumors. Recently, we developed radionuclide stimulated therapy that leverages the interaction of Cerenkov radiation emitting radionuclides to stimulate the production of reactive oxygen species from photosensitizers. The spatiotemporal therapeutic effects of these interactions allow the treatment of diverse diseases without tissue depth limitation that affects light-based therapies. Supported by new concepts grounded in robust preliminary data, we propose to (1) explore new nanostrategies to overcome the impediment to delivering NPs to tumors, (2) disrupt the protective interactions of cancer with stromal cells to enhance treatment response, and (3) exert sustainable therapeutic effect via multidimensional combination therapy to achieve disease-free survival. At the completion of this study, we would develop new nanoplatforms for the treatment and imaging of cancer and bone lesions.