Hafnium-Oxide Based Nanoplatform with Tumor Microenvironment Responsive Drug Release for Enhanced Radio-Chemotherapy

Purpose: Hafnium oxide nanoparticles have been established as effective radiosensitizers, however, tumor cells often develop resistance to single-modality radiotherapy, and the tumor microenvironment (TME) poses additional limitations to treatment efficacy. To address these challenges, we fabricated a doxorubicin and manganese oxide co-loaded hafnium oxide (MD-Hf) nanoplatform for synergistic radio-chemotherapy and evaluated its antitumor performance in cellular and animal models. Results: In MD-Hf nanoplatform, the HfO 2 nanocrystal functions as the radiosensitizer and carrier, the Dox works for chemotherapy, while the manganese oxide coating layer are capable of modulating the TME by depleting glutathione (GSH) and converting H 2 O 2 in to ·OH radicals. Moreover, the MnOx coating also allows the nanoplatform possessing TME-responsive Dox release. Upon exposure to X-rays, the MD-Hf exhibited evident toxicity to Panc 02 tumor cells, only 63.9±10.7% cell remain alive after irradiated with 2Gy X-ray, which is much lower than 86.7±6.33% of the group administrated with pure HfO 2 NPs. In vivo studies further demonstrated superior therapeutic outcomes with the MD-Hf nanoplatform, as evidenced by markedly reduced tumor size and weight compared to treatment with HfO 2 nanoparticles alone. RNA-seq analysis reveals the Dox can potentiate organelle damage, and the MnOx can even activate immune response, which further corroborates the multifunctionality of the integrated nanoplatform. Conclusion: The newly developed doxorubicin and manganese oxide co-loaded HfO 2 nanoplatform significantly enhance radio-chemotherapeutic efficacy against pancreatic tumor cells, offering a promising strategy that may guide the future clinical development of HfO 2 -based radiotherapy. Keywords: radiosensitizer, tumor microenvironment, drug release, radicals, nanoplatform