Traditional X-ray contrast media (XRCM) suffers from rapid renal clearance (half-life < 30 min), leading to a narrow acquisition time window for the X-ray computed tomography (CT) after intravenous (IV) administration, and limiting the operation time for the potential real-time CT-guided radiation therapy. Real-time image-guided radiation therapy can improve tumor-specific radiation dosages while sparing healthy tissue and critical structures. To broaden operational time and improve performance of XRCM, the next-generation XRCM with long blood residence time, high contrast efficiency, specific biodistribution, facile access to dual or multiple diagnostic imaging modalities, and biocompatibility is desirable. We report a simple strategy for preparing iodinated nano-XRCM for CT-PET dual imaging through intra/intermolecular self-assembly of random/statistical amphiphilic iodocopolymers (ICPs). ICPs were synthesized from reversible addition-fragmentation chain transfer (RAFT) copolymerization of triiodobenzoyl acrylate and oligo(ethylene oxide) acrylate monomers. The controlled RAFT copolymerization allowed for installation of DOTA moieties to chelate 64Cu radionuclides, enabling CT and positron emission tomography (PET) dual imaging and targeted radiotherapy. An EMT6 breast cancer mouse model (C57BL/6 mice) was used for in vivo biodistribution evaluation using 185 kBq of 64Cu-DOTA-ICP (45 mg/mouse) in 75 μL saline injected via the tail vein of C57BL/6 mice weighing 20–25 g (n = 4/group). The mice were euthanized at 1, 4, 24, and 48 h post-injection, and organs were collected, weighed, and counted in a well gamma counter. Intra/intermolecular self-assembly of ICPs formed nano-XRCM particles with ultrahigh iodine concentration (up to ca. 300 mg/mL), low viscosity (4.75 cSt at 37 °C), long term thermodynamic stability (> 6 months), and the identical hydrodynamic size of ca. 10 nm independent of the degree of polymerization. The resulting ICP-based nano-XRCMs showed excellent biocompatibility and exhibited long blood circulation time over 2 days with adequate tumor accumulation and low non-specific accumulation after single IV administration, allowing ample operation time for potential real-time CT image-guided radiation therapy application. Furthermore, the micro-CT imaging showed clear tumor contrast 6 days post-injection. The simple synthetic methodology allows the construction of multi-functional theranostic agents by incorporating diverse moieties. The ICP-based nano-XRCMs demonstrated extended blood residence time, high contrast efficiency, tumor specific accumulation, and biocompatibility for potential real-time image-guided radiotherapy application. Clear tumor contrast 6 days post-injection allowed convenient monitoring, which could be important for future studies of therapeutic effect.