Radiolabeled drug-delivery and controlled-release nanocarriers for arthritis: Clinical evidence, kinetic modeling, radiation-safety challenges, and precision nanotheranostics.

BACKGROUND: Arthritis comprises a heterogeneous group of inflammatory and degenerative joint disorders characterized by distinct pathological mechanisms, anatomical targets, and therapeutic requirements. Although arthritis is not primarily a pharmacokinetic disorder, several pharmacokinetic and delivery barriers can limit treatment. These include rapid synovial-fluid turnover, vascular and lymphatic clearance, heterogeneous pannus architecture, restricted cartilage penetration, protein-corona remodeling, mononuclear phagocyte system sequestration, and systemic toxicity after prolonged exposure. Radiolabeled controlled-release systems can transform drug-delivery evaluation by enabling quantitative measurement of carrier retention, payload disposition, extra-articular leakage, systemic biodistribution, target engagement, and absorbed radiation dose. OBJECTIVE: This review critically evaluates radiolabeled drug-delivery systems, particulate radionuclide therapies, and nanotheranostic strategies for arthritis, emphasizing formulation design, controlled-release kinetics, molecular targeting, radiochemical stability, clinical evidence, radiation safety, and translational feasibility. METHODS: A mechanistic narrative review was conducted using peer-reviewed clinical, translational, and preclinical studies addressing radiolabeled nanocarriers, intra-articular controlled-release platforms, radiosynoviorthesis, molecular imaging, biodistribution, dosimetry, and arthritis-targeted nanomedicine. Studies were prioritized when they reported experimentally determined physicochemical, pharmaceutical, pharmacokinetic, imaging, dosimetric, safety, or clinical-development data. Studies lacking an identifiable carrier, particulate, depot, or controlled-release component, as well as inadequately characterized radiochemical systems, were excluded from the comparative synthesis. RESULTS: Liposomes, biodegradable polymeric nanoparticles, micelles, macromolecular prodrugs, hydrogels, nanogels, cartilage-binding constructs, hydroxyapatite particles, radiocolloids, hybrid inorganic systems, and biomimetic carriers offer distinct combinations of synovial retention, drug-loading capacity, release behavior, and cellular or molecular targeting. Radiosynoviorthesis provides the strongest clinical precedent for particulate radionuclide therapy, demonstrating the importance of particle size, intra-articular distribution, radionuclide range, leakage control, and absorbed-dose heterogeneity. Human and translational evidence supports the relevance of prolonged joint residence and image-guided pharmacokinetic assessment, whereas most radiolabeled therapeutic nanocarriers remain at the preclinical or early translational stage. Major limitations include radiolabel instability, carrier-payload dissociation, radiation exposure, long-term nanomaterial safety, hepatic and splenic accumulation, manufacturing complexity, radionuclide availability, regulatory uncertainty, and limited cost-effectiveness evidence. Artificial intelligence-assisted image analysis, multimodal imaging, and patient-specific dosimetry may improve quantitative assessment and accelerate translation. CONCLUSIONS: Radiolabeling should be incorporated throughout controlled-release formulation development rather than used only as a final diagnostic component. The most credible translational strategy involves mechanism-matched platforms that combine stable radiochemistry, disease-relevant release kinetics, quantitative imaging, personalized dosimetry, rigorous safety assessment, reproducible manufacturing, and clinically meaningful superiority over conventional systemic or intra-articular therapy.