Imaging Modality, Not a Single Blueprint, Defines How Theranostics Work

Theranostics—the strategy of combining diagnostic imaging and therapy within a single platform—has moved far beyond its nuclear medicine origins, and a new narrative review argues that the choice of imaging modality fundamentally shapes how these systems are designed, how they function, and how close they are to clinical use. Published in European Radiology Experimental, the review examines theranostic approaches built on positron emission tomography (PET), single-photon emission computed tomography (SPECT), ultrasound, optical imaging, magnetic resonance imaging (MRI), and computed tomography (CT), and concludes that the field is expanding from modality-defined implementations toward integrated multimodal strategies.

The term “theranostics” was coined by John Funkhouser in 1998, but the underlying concept of image-guided therapy is much older. Radioiodine therapy was first applied in the early 1940s for hyperthyroidism, with the first clinical application published by Seidlin and colleagues. The arrival of SPECT cameras allowed imaging of iodine-131 and monitoring of the therapeutic intervention, establishing the pattern that defines the field today: the same chemical entity, or a closely matched pair of entities, serves both diagnosis and treatment.

Nuclear medicine remains the clinically established core of theranostics. The review highlights what it calls the “big three”: radioiodine therapy for thyroid disease, gallium-68/lutetium-177 DOTATATE (Lutathera) for neuroendocrine tumors, and gallium-68 PSMA-11 paired with lutetium-177 PSMA-617 (Pluvicto) for metastatic PSMA-positive prostate cancer. Additional approved approaches include iodine-123/131 Iobenguane (MIBG) for certain neuroendocrine tumors, radiolabeled antibodies, and radium-223 chloride (Xofigo). Regulatory approvals of Lutathera and Pluvicto by the US Food and Drug Administration have driven the concept into mainstream medical imaging, and the global theranostics market is projected to grow from roughly USD 2.1 billion in 2023 to around USD 4.3 billion by 2028, a compound annual growth rate of about 15.5 percent.

The authors identify four core frameworks that structure theranostic design across modalities: isotope-switch strategies in nuclear medicine, cavitation-driven approaches in ultrasound, carrier-based payload delivery systems, and activation-based mechanisms such as photodynamic therapy and radiosensitization. In the nuclear medicine case, the versatility of available radionuclides is key. The radiation provides the therapeutic effect while the targeting vector—a small molecule, peptide, protein, or antibody—determines where it acts. Ideally, diagnostic and therapeutic isotopes come from the same element, as with iodine or copper, forming what the authors call a “real theranostic pair.” Where the elements differ, as with gallium-68 paired with lutetium-177, the chemical differences are minimal and acceptable. A rule of thumb holds that the physical half-life of the isotope must match the biological half-life of the vector, so small molecules with fast kinetics pair with short-lived radionuclides while larger biologicals require longer-lived ones.

Most clinical innovation in radiotheranostics has focused on oncology, but the field is increasingly exploring non-cancer applications. Radiosynoviorthesis, in which radiocolloids are administered intra-articularly to treat inflammatory joints, is one example. In cardiology and neurodegenerative disorders, SPECT or PET scans inform and guide personalized clinical management, helping tailor conventional therapeutic interventions. The review notes that broader adoption of radiopharmaceutical theranostics is constrained by high production costs, limited availability, complex logistics, radiation safety requirements, and the need for specialized infrastructure and trained personnel.

Ultrasound-based theranostics rest on microbubbles, gas bodies of one to ten micrometers stabilized within albumin, lipid, or polymer shells, which scatter ultrasound waves to enhance contrast. Functionalized microbubbles can accumulate at pathological sites, enabling molecular ultrasound. Their therapeutic function arises directly through cavitation and sonoporation: cavitation—the formation, growth, and disruptive collapse of vapor-filled bubbles—can be spatially controlled so that incorporated drugs release only in the activated area. A notable example outside cancer therapy is sonothrombolysis, in which cavitation mechanically disrupts blood clots without any drug loading, meaning the same agent serves both diagnostic and therapeutic purposes; its affordability makes it suitable for pediatric applications. Sonoporation, the temporary formation of pores in cell membranes, is also being investigated to open tight junctions in the blood-brain barrier. More advanced agents include phase-change nanodroplets that vaporize into echogenic microbubbles under ultrasound, gas-generating nanoparticles, and sonosensitizers for sonodynamic therapy that produce reactive oxygen species upon activation. Clinical translation has been substantial, largely driven by approved microbubble contrast agents for cardiology and liver imaging, though limited penetration depth, acoustic window dependency, operator dependence, and the restriction of microbubbles to the intravascular space remain constraints.

CT-based theranostics are comparatively underrepresented, but CT-guided approaches have advanced to clinical trials. The leading candidates are high atomic number nanoparticles, particularly hafnium oxide (HfO2), whose high X-ray attenuation makes it an effective CT contrast agent while also enabling radiosensitization: when irradiated during external radiotherapy, hafnium produces local dose enhancement via secondary electrons. A recently published clinical trial of the HfO2-based radiosensitizer NBTXR3 in a cohort of 180 patients validated its mode of action. Iodinated compounds offer a heavy-metal-free alternative, including iodine-containing covalent organic frameworks that function as radiosensitizers. The review positions CT as a structural and quantitative partner in multimodal theranostic systems rather than a standalone platform, noting that CT’s low molecular sensitivity requires high concentrations of heavy-metal materials, raising concerns about systemic exposure, long-term retention, and dose-related toxicity.

MRI theranostics remain largely translational despite high spatial resolution, deep tissue penetration, and repeated longitudinal imaging without ionizing radiation. The field divides into molecular MRI theranostics, based on small-molecule or coordination-based agents using paramagnetic ions such as gadolinium and manganese or nuclei such as fluorine-19, and MRI nanotheranostics built on nanoscale carriers like polymeric nanoparticles, iron oxide particles, and dendrimers. Magnetite nanoparticles are among the most advanced: the FDA-approved iron oxide formulation ferumoxytol has been repurposed for vascular and inflammatory imaging, while NanoTherm, approved by the European Medicines Agency for brain tumors, and Magnablate exemplify theranostic hyperthermia applications under clinical evaluation. Gadolinium oxide nanoparticles show strong contrast at reduced gadolinium doses in preclinical studies but have not achieved clinical translation. MRI’s comparatively low sensitivity requires high local concentrations of contrast agents, limiting molecular theranostics with therapeutically relevant payloads and favoring nanoscale systems with their associated complexity.

Optical theranostics offer excellent molecular sensitivity and activatable, mechanism-driven designs but are inherently constrained by limited penetration depth from light scattering and absorption. Photodynamic therapy, in which the same photosensitizer mediates both imaging and therapy by generating reactive oxygen species upon light excitation, has achieved clinical adoption in dermatology, ophthalmology, and oncology for superficial or endoluminal lesions. Photothermal theranostics using gold nanoparticles and strongly near-infrared-absorbing dyes, and nanoparticle-based systems carrying chemotherapy, gene delivery, or immunomodulation payloads, remain mostly preclinical or early translational. Emerging multimodal strategies extend these capabilities: photoacoustic theranostics combine optical absorption sensitivity with ultrasound’s penetration and resolution, while Raman and surface-enhanced Raman scattering platforms provide highly multiplexed molecular detection using plasmonic nanoparticles, though both remain limited to surface-accessible, endoscopic, or intraoperative settings and, in the case of photoacoustic and Raman approaches, are currently confined to basic research applications.

The review’s central message is that theranostics is determined by the underlying imaging modality rather than by a unified framework, and that imaging modality dictates the integration strategy. Nuclear medicine theranostics are clinically established, while MRI-, CT-, ultrasound-, and optical-based systems remain largely translational or function primarily as image-guided therapies. Multimodal theranostics address modality-specific limitations by combining complementary technologies, and future progress, the authors argue, depends on imaging-driven design and standardization. As vector engineering, smart and scalable material platforms, quantitative imaging technologies, and regulatory harmonization advance, multimodal theranostics are increasingly positioned to play a central role in precision medicine, enabling more personalized, adaptive, and effective image-guided therapies.

Subject of Research: How imaging modality shapes the design and clinical maturity of theranostic platforms

Article Title: Beyond radiotheranostics: how imaging modality defines theranostics

Article References: Pashkunova-Martic, I., Pichler, V., & Helbich, T. H. (2026). Beyond radiotheranostics: how imaging modality defines theranostics. European Radiology Experimental, 10(1), Article 152. https://doi.org/10.1186/s41747-026-00823-x

Image Credits: AI Generated

DOI: 10.1186/s41747-026-00823-x

Keywords: theranostics, PET, SPECT, ultrasound, MRI, computed tomography, optical imaging, radiopharmaceuticals, microbubbles, nanoparticles, photodynamic therapy, multimodal imaging