Nanomedicine has stepped into the spotlight of radiation therapy over the last two decades. Nanoparticles (NPs), especially metallic NPs, can potentiate radiotherapy by specific accumulation into tumors, thus enhancing the efficacy while alleviating the toxicity of radiotherapy. Water radiolysis is a simple, fast and environmentally-friendly method to prepare highly controllable metallic nanoparticles in large scale. In this study, we used this method to prepare biocompatible PEGylated (with Poly(Ethylene Glycol) diamine) platinum nanoflowers (Pt NFs). These nanoagents provide unique surface chemistry, which allows functionalization with various molecules such as fluorescent markers, drugs or radionuclides. The Pt NFs were produced with a controlled aggregation of small Pt subunits through a combination of grafted polymers and radiation-induced polymer cross-linking. Confocal microscopy and fluorescence lifetime imaging microscopy revealed that Pt NFs were localized in the cytoplasm of cervical cancer cells (HeLa) but not in the nucleus. Clonogenic assays revealed that Pt NFs amplify the gamma rays induced killing of HeLa cells with a sensitizing enhancement ratio (SER) of 23%, thus making them promising candidates for future cancer radiation therapy. Furthermore, the efficiency of Pt NFs to induce nanoscopic biomolecular damage by interacting with gamma rays, was evaluated using plasmids as molecular probe. These findings show that the Pt NFs are efficient nano-radio-enhancers. Finally, these NFs could be used to improve not only the performances of radiation therapy treatments but also drug delivery and/or diagnosis when functionalized with various molecules.

Metallic nanoparticles (NPs) and ultra‐high dose rate (UHDR, FLASH) irradiation are being developed to widen the therapeutic index of radiotherapy, but their interaction remains poorly defined. We assessed PEGylated platinum nanoparticles (Pt‐NPs) in 4T1 tumor spheroids and syngeneic 4T1 and MC38 mouse models exposed to conventional (CONV, 0.125 Gy/s) or UHDR electron irradiation (∼200 Gy/s mean dose rate). Pt‐NPs penetrated throughout 4T1 spheroids and were mainly cytoplasmic. In clonogenic assays, Pt‐NPs increased radiation‐induced loss of reproductive capacity under both dose‐rate conditions. LQ analysis suggested dose‐dependent divergence between modalities, with significantly greater radioenhancement under UHDR only at 12 Gy (SER: 65.9% vs 40.8%, ΔSER = 25.1 percentage points, 95% CI, 2.1–48.1, p = 0.034). Pt‐NPs did not measurably alter apoptosis or γ‐H2AX kinetics. Micro‐CT confirmed intratumoral platinum at irradiation, but in vivo responses were heterogeneous. Pt‐NPs did not improve tumor control in the poorly immunogenic 4T1 model. In the more radiosensitive MC38 model, Pt‐NPs showed a nonsignificant trend toward improved tumor control and survival under CONV, with no comparable UHDR benefit. These findings identify an in vitro‐to‐in vivo disconnect and show that NP radioenhancement cannot be assumed to translate across dose‐rate regimens, tumor models, or host backgrounds.