Intermetallic nanoassemblies potentiate systemic STING activation.

Area of Science:

• Biomedical Engineering
• Immunology
• Nanotechnology

Background:

• Natural systems inspire nanotherapeutics using metal ions for biological regulation.
• The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is crucial for antitumor immunity.
• Systemic activation of the STING pathway is challenging due to poor pharmacology and toxicity.

Purpose of the Study:

• To develop a structurally ordered intermetallic nanoparticle, CRYSTAL, for potent systemic STING activation.
• To evaluate the safety and efficacy of CRYSTAL in preclinical models and non-human primates.

Main Methods:

• CRYSTAL nanoparticles were self-assembled from manganese ions and cyclic dinucleotides.
• Systemic administration of CRYSTAL at an ultralow intravenous dose (0.003 mg/kg).
• Assessment of STING activation, cytokine release, tumor regression, immune microenvironment remodeling, and T cell priming in various animal models and human biopsies.

Main Results:

• CRYSTAL achieved precise structural control and potent systemic STING activation in mice, dogs, and nonhuman primates.
• No cytokine release syndrome was observed at ultralow doses.
• Robust tumor regression in advanced murine and rabbit models, with STING-dependent CD8+ T cell priming.
• Activation of interferon responses in human head and neck squamous cell carcinoma biopsies.

Conclusions:

• CRYSTAL represents a novel nanotherapeutic for potent systemic STING activation.
• The nanoparticle demonstrates a favorable safety profile and significant therapeutic potential for cancer immunotherapy.
• CRYSTAL's ability to remodel the tumor microenvironment and prime T cell responses highlights its translational promise.