Design principles of inorganic and carbon-based radiopharmaceutical nanoparticles for targeted cancer therapy: Stability, functionalization, and translational perspectives

Inorganic and carbon-based radiopharmaceutical nanoparticles are emerging as versatile platforms for targeted cancer imaging, radionuclide therapy, and theranostics because their composition, architecture, surface chemistry, and radiolabeling strategy can be engineered to control radiochemical stability and biological fate. However, many reported systems remain at the proof-of-concept stage, and their translation is limited by radiolabel leakage, daughter-nuclide redistribution, protein corona formation, reticuloendothelial-system sequestration, heterogeneous tumor penetration, limited dosimetric evaluation, and manufacturing complexity. This review provides a materials-centered design-principles framework for radiopharmaceutical nanoparticles, integrating metallic, metal oxide, silica, carbon-based, and hybrid nanostructures. We critically compare chelation-based and chelator-free radiolabeling strategies, including their behavior in biological media, transchelation risk, isotope leaching, and suitability for theranostic applications. We further discuss how nanoparticle size, morphology, surface charge, coating chemistry, ligand density, and radiolabeling route influence biodistribution, tumor-to-organ ratios, clearance, toxicity, and absorbed-dose distribution. Particular attention is given to nano–bio interface barriers, including protein corona formation, cellular uptake, intracellular trafficking, exocytosis, and tumor microenvironment constraints that limit nanoparticle penetration and therapeutic dose delivery. Next-generation approaches, including core–shell radionuclide confinement, stimuli-responsive designs, AI-guided optimization, renal-clearable platforms, and EPR-independent targeting strategies, are evaluated in relation to radiopharmaceutical-specific requirements rather than general nanomedicine trends. Finally, we outline translational criteria involving quantitative dosimetry, standardized preclinical readouts, automated GMP-compatible manufacturing, surface-conjugation reproducibility, clinical-stage evidence, and regulatory considerations. By linking materials chemistry with radiochemical integrity, biological performance, dosimetry, and manufacturability, this review provides a practical framework for prioritizing clinically relevant radiopharmaceutical nanoparticle designs.