Radiation therapy remains a cornerstone in cancer treatment, but its efficacy is often limited by the need to spare healthy tissues while delivering sufficient doses to tumors. The integration of high-atomic-number (high-Z) nanomaterials as radiosensitizers has emerged as a promising strategy to enhance the therapeutic ratio. Among these, gold nanoparticles (AuNPs) and hafnium oxide nanoparticles (HfO2 NPs) have shown significant potential due to their unique physical and chemical properties. These nanoparticles amplify radiation effects through mechanisms such as Auger electron emission, Compton scattering, and photoelectric absorption, leading to localized dose enhancement. Their compatibility with modern radiation modalities, including proton therapy, further underscores their clinical relevance.

The radiosensitizing effect of high-Z nanoparticles arises from their strong interaction with ionizing radiation. When exposed to X-rays or gamma rays, gold (Z=79) and hafnium (Z=72) exhibit high cross-sections for photoelectric absorption, leading to the ejection of inner-shell electrons. The subsequent relaxation of excited atoms results in the emission of Auger electrons and characteristic X-rays. Auger electrons, in particular, are low-energy electrons that deposit their energy within nanometers of their origin, causing highly localized DNA damage. This process is especially effective in nanoparticles due to their high surface-to-volume ratio, which maximizes interactions with surrounding cellular structures. Compton scattering also contributes to dose enhancement, as high-Z materials scatter photons more efficiently, increasing energy deposition within the tumor.

Dose enhancement factors (DEF) quantify the increase in radiation effects due to nanoparticle presence. Studies have reported DEF values ranging from 1.2 to 2.5 for gold nanoparticles, depending on nanoparticle concentration, size, and radiation energy. Hafnium oxide nanoparticles exhibit similar enhancements, with DEF values influenced by their crystalline structure and surface modifications. For instance, HfO2 NPs with optimized surface coatings achieve DEF values comparable to AuNPs while offering improved biocompatibility and reduced toxicity. The DEF is also energy-dependent, with lower-energy photons (e.g., 50–150 keV) showing greater enhancement due to the dominance of photoelectric effects.

Targeted delivery of nanoparticles to tumors is critical for maximizing radiosensitization while minimizing off-target effects. Passive targeting exploits the enhanced permeability and retention (EPR) effect, where nanoparticles accumulate in tumor tissue due to leaky vasculature and poor lymphatic drainage. Active targeting involves functionalizing nanoparticles with ligands such as antibodies, peptides, or small molecules that bind to overexpressed receptors on cancer cells. For example, AuNPs conjugated with epidermal growth factor receptor (EGFR) antibodies selectively localize in EGFR-positive tumors. Similarly, HfO2 NPs coated with polyethylene glycol (PEG) exhibit prolonged circulation times and improved tumor uptake. Advances in imaging techniques, such as computed tomography (CT) and positron emission tomography (PET), enable real-time tracking of nanoparticle distribution, ensuring precise delivery.

Clinical translation of nanoparticle radiosensitizers has progressed significantly, with hafnium oxide nanoparticles leading the way. NBTXR3, a suspension of crystalline HfO2 NPs, has undergone extensive evaluation in phase I–III trials. In a phase I study involving patients with advanced soft tissue sarcoma, intratumoral injection of NBTXR3 followed by radiotherapy demonstrated a favorable safety profile and significant tumor regression. A subsequent phase III trial confirmed improved local control and progression-free survival compared to radiotherapy alone. Similar trials are underway for head and neck, prostate, and liver cancers, with preliminary results indicating enhanced therapeutic outcomes. Gold nanoparticles are also being investigated, though their clinical development has been slower due to challenges in large-scale synthesis and standardization.

The compatibility of high-Z nanoparticles with proton therapy is an area of growing interest. Proton beams offer superior dose conformity compared to photons, but their biological effectiveness can be further augmented by nanoparticles. Unlike photons, protons interact with nanoparticles primarily through Coulomb forces, leading to secondary electron emission and increased linear energy transfer (LET). Preclinical studies demonstrate that AuNPs and HfO2 NPs enhance proton therapy efficacy, particularly in hypoxic tumors where traditional radiation is less effective. The combination of nanoparticles with proton beams also reduces the risk of distal dose deposition, a critical advantage for sparing healthy tissues. Ongoing research aims to optimize nanoparticle formulations for proton therapy, focusing on size, concentration, and surface chemistry.

Despite the promise of nanoparticle radiosensitizers, several challenges remain. Long-term toxicity, biodistribution, and immune responses require further investigation. The scalability of nanoparticle production and sterilization processes must be addressed to meet clinical demands. Additionally, the interplay between nanoparticle properties and radiation parameters necessitates personalized treatment planning. Computational models are being developed to predict dose enhancement and optimize nanoparticle-radiation combinations for individual patients.

In summary, gold and hafnium oxide nanoparticles represent a transformative approach to enhancing radiation therapy. Their ability to amplify radiation effects through well-defined physical mechanisms, coupled with advances in targeted delivery and clinical validation, positions them as key players in oncology. The ongoing integration of these nanomaterials with cutting-edge modalities like proton therapy underscores their potential to redefine cancer treatment paradigms. Future research will focus on refining nanoparticle designs, expanding clinical applications, and addressing translational challenges to fully realize their therapeutic benefits.