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 (Dy 2 O 3 -T) featuring a uniform hollow architecture, defect-rich lattice, and abundant oxygen vacancies. These features enable accelerated Dy 3+ ion release and efficient lysosome-specific biotransformation into dysprosium phosphonate salts. Compared with commercial Dy 2 O 3 , which had already demonstrated promising activity, Dy 2 O 3 -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 Dy 2 O 3 -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 Dy 2 O 3 -T as a structurally engineered REO nanoplatform bridging precision REO nanomaterials engineering with potent cancer immunotherapy in vivo .