Design of a rare-earth-based nanotherapeutic platform for pyroptosis-mediated cancer immunotherapy

Rare-earth oxides (REOs) show promise as immunomodulators, yet the structural determinants of their biological activity remain unclear. We report a hydrothermal self-assembled dysprosium oxide nanotube assembly (Dy₂O₃-T) featuring a uniform hollow architecture, defect-rich lattice, and abundant oxygen vacancies. These features enable accelerated Dy³⁺ ion release and efficient lysosome-specific biotransformation into dysprosium phosphonate salts. Compared with commercial Dy₂O₃, which had already demonstrated promising activity, Dy₂O₃-T demonstrated superior activity in inducing gasdermin E (GSDME)-dependent pyroptotic cell death (PyCD) in experimental mammary tumor-6 (EMT6) breast cancer models via a caspase-3 pathway. In vivo, intratumoral administration of Dy₂O₃-T triggered pyroptosis-driven tumor immunogenicity in the GSDME^high EMT6 tumors, potentiated by anti-programmed cell death protein 1 (anti-PD-1) blockade. Importantly, in GSDME^low 4T1 tumors, co-delivery of GSDME mRNA via lipid nanoparticles reinstated PyCD and immune activation, overcoming resistance associated with GSDME deficiency. These findings highlight Dy₂O₃-T as a structurally engineered REO nanoplatform bridging precision REO nanomaterials engineering with potent cancer immunotherapy in vivo.