Hepatocellular carcinoma (HCC) is the most common primary liver cancer that represents the second most common cause of cancer-related death worldwide. In addition, the liver the most common site for metastatic cancer. Transarterial chemo- or radio-embolization (TACE/TARE) for unresectable HCC exploits the hepatic tumors’ blood supply via the hepatic artery to selectively deliver the embolic agents and therapeutics into targeted region of the liver. However, these treatments are largely palliative and direct visualization of the delivery after contrast washout is not possible. Thus, new theranostic modalities are urgently needed. Alpha- emitting radiopharmaceutical therapy (αRPT) is emerging as a highly potent treatment that effectively targets single cells, minimal residual disease, and micrometastatic lesions to eradicate cancer cells that exhibit resistance to conventional treatment. To address diffusion-limited penetration depths of αRPT that may result in partial tumor irradiation, we propose to develop a dual modality imaging-visible, exosome-mediated radiotheranostic platform for an alpha emitter delivery. In Specific Aim 1, we will evaluate the imaging visibility and targeting ability of radiolabeled exosomes in cell monolayers and 3D vascularized spheroids. A selected αRPT formulation will be tested in ectopic and orthotopic HCC mouse models (Aim 2), allowing us to evaluate its biodistribution, efficacy and safety via intratumoral and intraarterial delivery. The proposed study brings a unique combination of expertise in radiosynthesis, dosimetry, medical imaging, and animal model of cancers, to address the critical challenges for effective HCC treatment. Successful completion of the proposed activities will have vast ramifications for advancing the development of exosome-mediated αRPT for treating HCC or other cancers.