Abstract

Background: Resistance to radiotherapy (RT) remains a significant obstacle in the management of central nervous system (CNS) tumors, including glioblastoma, medulloblastoma, ependymoma, and brain metastases. These malignancies often exhibit robust DNA repair mechanisms and poor treatment selectivity, leading to suboptimal therapeutic efficacy and collateral damage to healthy brain tissue. Functionalized nanoparticles (NPs) have emerged as a promising strategy to enhance radiosensitivity, enable image-guided therapy, and protect non-tumoral tissue, offering a pathway toward personalized neuro-oncology.

Objectives: To systematically assess the efficacy, specificity, and safety of targeted nanoparticles as radiosensitizers and theranostic agents in CNS tumors treated with radiotherapy.

Methods: This systematic review followed the PRISMA 2020 guidelines. We searched PubMed, and ClinicalTrials.gov up to May 2025 for preclinical and clinical studies evaluating functionalized nanoparticles—such as gadolinium- based agents (AGuIX®), siRNA-loaded systems targeting Ape1, silver nanoparticles (AgNPs), and ecdysteroid- based conjugates—in CNS tumors undergoing radiotherapy. Eligibility criteria included experimental studies with quantifiable radiotherapy outcomes (e.g., survival, clonogenic death, DNA damage). Data were synthesized qualitatively due to heterogeneity in models and outcomes.

Results: Nine studies met inclusion criteria: six preclinical (murine models and in vitro CNS tumor lines) and three clinical (phases I–II). siRNA-loaded NPs targeting the base excision repair enzyme Ape1 showed >75% knockdown efficiency and significantly enhanced radiosensitivity in glioblastoma and pediatric tumor models, doubling survival rates in murine models compared to RT alone. AGuIX® NPs demonstrated dual MRI contrast enhancement and radiosensitization, with increased tumor delineation and survival gains in both animals and patients with brain metastases. AgNPs potentiated oxidative stress-induced DNA damage via ROS production, while ecdysteroid-based NPs selectively sensitized tumor cells to RT and preserved normal cell viability. Across studies, NP-RT combinations led to 2–3× improved therapeutic indices compared to standard RT, with no observed increase in systemic toxicity. Conclusions: Targeted nanoparticles enhance the precision and effectiveness of radiotherapy in CNS tumors through mechanisms such as inhibition of DNA repair, oxidative damage amplification, and imaging-guided targeting. These results support the integration of NP-based platforms in neuro-oncology protocols to personalize radiotherapy, minimize off-target effects, and overcome resistance. The reviewed evidence justifies further development of these systems in large-scale clinical trials, especially in patients with tumors refractory to conventional treatments.