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

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.

In MD-Hf nanoplatform, the HfO₂ 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 H₂O₂ 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 HfO₂ 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 HfO₂ 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.

The newly developed doxorubicin and manganese oxide co-loaded HfO₂ nanoplatform significantly enhance radio-chemotherapeutic efficacy against pancreatic tumor cells, offering a promising strategy that may guide the future clinical development of HfO₂-based radiotherapy.