Data from: Intermetallic nanoassemblies potentiate systemic STING activation

Natural systems utilize metal ions in structurally ordered architectures
to regulate essential biological processes, inspiring the rational design
of nanostructures for therapeutic applications. The cGAS-STING pathway, a
key mediator of innate immunity, detects cytoplasmic DNA and triggers type
I interferon (IFN-I) responses essential for antitumor immunity. However,
translating STING activation into effective cancer immunotherapy has been
challenging due to poor pharmacological properties and systemic toxicity.
Here, we report CRYSTAL (Crystal-like STING-Activating nanoassemblies), a
structurally ordered intermetallic nanoparticle platform for potent
systemic STING activation. CRYSTAL was synthesized via self-assembly of
manganese (Mn2+) ions intercalated with cyclic dinucleotides, wrapped
within lipid layers. Computational modeling accurately predicted CRYSTAL’s
self-assembly behavior, highlighting its tunability and design precision.
At ultra-low doses, intravenous CRYSTAL administration effectively
activated STING in mice, dogs, and non-human primates, and CRYSTAL
demonstrated remarkable antitumor efficacy in late-stage murine and rabbit
tumor models. Mechanistically, CRYSTAL reversed immunosuppressive tumor
and spleen microenvironments and triggered robust CD8+ T cell priming in a
host STING dependent manner. CRYSTAL also induced IFN-I responses in human
head and neck squamous cell carcinoma (HNSCC) biopsies, underscoring its
translational potential. These findings establish structurally ordered
metallo-nanostructures as a promising strategy for metalloimmunotherapy.