Radiotherapy is a key pillar of solid cancer treatment. Despite a high level of conformal dose deposition, radiotherapy is limited due to co-irradiation of organs at risk and subsequent normal tissue toxicities. Nanotechnology offers an attractive opportunity for increasing the efficacy and safety of cancer radiotherapy. Leveraging the freedom of design and the growing synthetic capabilities of the nanomaterial-community, a variety of engineered nanomaterials have been designed and investigated as radiosensitizers or radioenhancers. While research so far has been primarily focused on gold nanoparticles and other high atomic number materials to increase the absorption cross section of tumor tissue, recent studies are challenging the traditional concept of high-Z nanoparticle radioenhancers and highlight the importance of catalytic activity. This review provides a concise overview on the knowledge of nanoparticle radioenhancement mechanisms and their quantification. It critically discusses potential radioenhancer candidate materials and general design criteria for different radiation therapy modalities, and concludes with research priorities in order to advance the development of nanomaterials, to enhance the efficacy of radiotherapy and to increase at the same time the therapeutic window.

Bright, stable, and biocompatible fluorescent contrast agents operating in the second biological window (1000–1350 nm) are attractive for imaging of deep‐lying structures (e.g., tumors) within tissues. Ideally, these contrast agents also provide functional insights, such as information on local temperature. Here, water‐dispersible barium phosphate nanoparticles doped with Mn⁵⁺ are made by scalable, continuous, and sterile flame aerosol technology and explored as fluorescent contrast agents with temperature‐sensitive peak emission in the NIR‐II (1190 nm). Detailed assessment of their stability, toxicity with three representative cell lines (HeLa, THP‐1, NHDF), and deep‐tissue imaging down to about 3 cm are presented. In addition, their high quantum yield (up to 34%) combined with excellent temperature sensitivity paves the way for concurrent deep‐tissue imaging and nanothermometry, with biologically well‐tolerated nanoparticles.

Nano-sized metal organic frameworks (nanoMOFs) have gained increasing importance in biomedicine due to their tunable properties. In addition to their use as carriers in drug delivery, nanoMOFs containing hafnium have been successfully employed as radio-enhancers augmenting damage caused by X-ray irradiation in tumor tissue. While results are encouraging, there is little mechanistic understanding available, and the biological fate of these radio-enhancer nanoparticles remains largely unexplored. Here, we synthesized a selection of group IV metal-based (Hf, Ti, Ti/Zr) nanoMOFs and investigated their cell compatibility and radio-enhancement performance in direct comparison to the corresponding metal oxides. We report surprising radio-enhancement performance of Ti-containing nanoMOFs reaching dose modifying ratios of 3.84 in human sarcoma cells and no relevant dose modification in healthy human fibroblasts. These Ti-based nanoMOFs even outperformed previously reported Hf-based nanoMOFs as well as equimolar group IV metal oxides in direct benchmarking experiments. While group IV nanoMOFs were well-tolerated by cells in the absence of irradiation, the nanoMOFs partially dissolved in lysosomal buffer conditions showing distinctly different chemical stability compared to widely researched group IV oxides (TiO₂, ZrO₂, and HfO₂). Taken together, this study illustrates the promising potential of Ti-based nanoMOFs for radio-enhancement and provides insight into the intracellular fate and stability of group IV nanoMOFs.

Ti ₃ C ₂ T _x MXenes, introduced in tumor tissues, amplify X-ray interactions to increase reactive oxygen species production, leading to higher cancer cell death and potentially improved radiotherapy results.

Engineering of catalytically active inorganic nanomaterials holds promising prospects for biomedicine. Catalytically active metal oxides show applications in enhancing wound healing but have also been employed to induce cell death in photodynamic or radiation therapy. Upon introduction into a biological system, nanomaterials are exposed to complex fluids, causing interaction and adsorption of ions and proteins. While protein corona formation on nanomaterials is acknowledged, its modulation of nanomaterial catalytic efficacy is less understood. In this study, proteomic analyses and nano‐analytic methodologies quantify and characterize adsorbed proteins, correlating this protein layer with metal oxide catalytic activity in vitro and in vivo. The protein corona comprises up to 280 different proteins, constituting up to 38% by weight. Enhanced complement factors and other opsonins on nanocatalyst surfaces lead to their uptake into macrophages when applied topically, localizing >99% of the nanomaterials in tissue‐resident macrophages. Initially, the formation of the protein corona significantly reduces the nanocatalysts' activity, but this activity can be partially recovered in endosomal conditions due to the proteolytic degradation of the corona. Overall, the research reveals the complex relationship between physisorbed proteins and the catalytic characteristics of specific metal oxide nanoparticles, providing design parameters for optimizing nanocatalysts in complex biological environments.

Nanoparticle radioenhancement offers a promising strategy for augmenting radiotherapy by locally increasing radiation damage to tumor tissue. While past research has predominantly focused on nanomaterials with high atomic numbers, such as Au and HfO ₂ , recent work has revealed that their radioenhancement efficacy decreases considerably when using clinically relevant megavoltage X‐rays as opposed to the orthovoltage X‐rays typically employed in research settings. Here, radiocatalytically active Ti‐based nanomaterials for clinical X‐ray therapy settings are designed. A range of candidate materials, including TiO ₂ (optionally decorated with Ag or Pt nanoseeds), Ti‐containing metal–organic frameworks (MOFs), and 2D Ti‐based carbides known as Ti ₃ C ₂ T _x MXenes, is investigated. It is demonstrated that these titanium‐based candidates remain consistently performant across a wide energy spectrum, from orthovoltage to megavoltage. This sustained performance is attributed to the catalytic generation of reactive oxygen species, moving beyond the simple physical dose enhancements associated with photoelectric effects. Beyond titania, emergent materials like titanium‐based MOFs and MXenes exhibit encouraging results, achieving dose‐enhancement factors of up to three in human soft tissue sarcoma cells. Notably, these enhancements are absent in healthy human fibroblast cells under similar conditions of particle uptake, underscoring the selective impact of titanium‐based materials in augmenting radiotherapy across the clinically relevant spectral range.