Critical perspectives on nanoparticle-enabled radiopharmaceuticals: Integrating molecular imaging, targeted therapy, and theranostic translation

Radiopharmaceuticals based on nanoparticles are transforming the landscape of molecular imaging, targeted therapy and theranostics. Nevertheless, despite the accelerating innovation, translation is still being challenged with lack of uniformity, regulatory vagueness, and lack of universal access. There is a pressing need to realize the potential of technology in a critical synthesis to bring together the technological promise and clinical feasibility and equity. The evidence synthesis framework followed in this review was PRISMA, which involved identification and appraisal of preclinical and clinical studies in large databases (2000–2025). The approach of evidence-based mapping fused with the methodology of critical appraisal which encompassed the following domains: radiochemistry, imaging performance, dosimetry, safety, manufacturing, and regulatory preparedness. Matrices of comparative evidence and translational readiness models (TRL-R) were created to determine the progress and gaps that have not been reached yet. Nano-radiopharmaceuticals have better versatility of payload, multimodal imaging and personalized dosimetry could be used. Among the major mechanistic barriers, protein corona dynamics can alter nanoparticle surface identity, masking targeting ligands and reducing receptor-specific uptake. Similarly, tumor microenvironment (TME) resistance, including dense extracellular matrix and abnormal vasculature, limits nanoparticle penetration and uniform drug distribution. Together, these mechanisms diminish drug bioavailability and therapeutic efficacy within tumor tissues. The other limiting factor to translation is bottlenecks in supply of isotopes, asymmetries in cost, and trial designs not harmonized. The upcoming opportunities are green radiochemistry, AI-based dosimetry, smart activatable nanoparticles, and combinations with immuno- and cell therapies. The problems of equity, particularly in low-middle income countries (LMICs), require the efforts of isotope access innovations, cost-sharing systems, and inclusive trial systems. The nano-radiopharmaceuticals are at a leadership and weak frontier. Several standards that should be developed to advance toward global clinical adoption include the standards on reproducibility, sustainable isotope supply chains, and open science infrastructures and equity-oriented trial designs. A gradual research plan- short, mid and long term- can trigger sustainable, safe and universally obtainable theranostic translation.