Functionalized Nanocarriers for Tumor-Selective Radiosensitization and Drug Delivery in Cancer Radiotherapy: A Systematic Review

Running title: Tumor-Targeted Nanocarriers for Radiotherapy

Abstract

Background: The aim of this study is to provide a comprehensive review of recent advances in the application of nanocarriers for targeted drug delivery and radiosensitization in cancer radiotherapy (RT), as well as to examine the challenges, solutions, and future prospects of this technology.

Methods: A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, and Embase, identifying 373 records. Following PRISMA guidelines, 36 studies met inclusion criteria focusing on functionalized nanocarriers in cancer RT. Data extraction covered nanoparticle types, functionalization, therapeutic payloads, cancer models, radiation modalities, and outcomes.

Results: Forty studies were analyzed, categorized into iron oxide-based (10), silver (10), bismuth-based (7), graphene-based (4), gadolinium-based (4), and titanium-based (2) nanoparticles (NPs). Bismuth-based NPs (BiNPs) showed superior radiosensitization with sensitizer enhancement ratios (SERs) of 1.25–1.48 and up to 450% reactive oxygen species (ROS) increase in vivo, achieving ~70% tumor volume reduction without systemic toxicity. Silver NPs (AgNPs) demonstrated dose enhancement factors (DEF) rising from 1.4 to 1.9 and synergistic effects with docetaxel plus 2 Gy radiation. Iron oxide NPs functionalized with HER2 and RGD ligands reduced cell viability by 1.95-fold and achieved DEF of 89.1 in targeted systems. Gadolinium NPs reached SERs up to 2.44 at 65 keV, while graphene-based systems enhanced ROS production by 75.2%. Titanium-based NPs increased ROS levels 2.5-fold. Combination therapies integrating chemotherapeutics such as cisplatin and curcumin with nanocarriers yielded SERs up to 4.29. Radiation modalities included megavoltage X-rays (4–10 MV, n=24), synchrotron keV X-rays (n=2), gamma rays (0.38–1.25 MeV, n=3), and electron beams (6–12 MeV, n=3).

Conclusions: Bismuth-based NPs represent the most promising radiosensitizers due to their high efficacy, safety, and clinical relevance, supporting their advancement toward clinical translation.