Zhou, and Ling et al. engineered CRYSTAL, a crystal-like STING-activating nanoassembly, to stabilize a STING agonist and enhance STING signaling at lower doses. Intravenous CRYSTAL activated myeloid cells, remodeled immunosuppressive tumor microenvironments, and primed host STING-dependent CD8+ T cell responses, driving durable tumor regression in advanced murine and rabbit models. Across mice, dogs, and non-human primates, CRYSTAL induced potent, but transient interferon responses, without cytokine release syndrome. Ex vivo treatment of human head and neck cancer biopsies triggered strong interferon signaling.
Contributed by Shishir Pant
Xingwu Zhou # 1 2, Xiang Ling # 1 2, Xiaoqi Sun 1 2, Ziye Wan 1 2, Tobias Dwyer 3, Timothy C Moore 3, Quguang Li 1 2, Hannah E Dobson 1 2, Qi Wu 1 2, Xiangbo Kong 4, Fang Xie 1 2, Xinran An 1 2, Jingyao Gan 1 2, Kaikai Wang 1 2, Young Seok Cho 1 2, Wang Gong 5, Katherine Dong 1 2, Jie Zhang 1 2, Mariko Takahashi 1 2, Cheng Xu 1 2, Swetha Kodamasimham 1 2, Jie Xu 4, Vilma Yuzbasiyan-Gurkan 6 7, Steven B Chinn 8, Anna Schwendeman 1 2, Sharon C Glotzer 2 3, Yu Leo Lei 5, James J Moon 1 2 3 9 10
Zhou, and Ling et al. engineered CRYSTAL, a crystal-like STING-activating nanoassembly, to stabilize a STING agonist and enhance STING signaling at lower doses. Intravenous CRYSTAL activated myeloid cells, remodeled immunosuppressive tumor microenvironments, and primed host STING-dependent CD8+ T cell responses, driving durable tumor regression in advanced murine and rabbit models. Across mice, dogs, and non-human primates, CRYSTAL induced potent, but transient interferon responses, without cytokine release syndrome. Ex vivo treatment of human head and neck cancer biopsies triggered strong interferon signaling.
Contributed by Shishir Pant
ABSTRACT: Natural systems use metal ions to form ordered structures that regulate biological processes, inspiring the rational design of nanotherapeutics. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway drives antitumor immunity but has been difficult to activate systemically owing to poor pharmacology and toxicity. Here, we report CRYSTAL, a structurally ordered intermetallic nanoparticle for potent systemic STING activation. CRYSTAL self-assembles from manganese ions intercalated with cyclic dinucleotides, enabling precise structural control. At an ultralow intravenous dose (0.003 milligrams per kilogram), CRYSTAL activated STING in mice, dogs, and nonhuman primates without cytokine release syndrome. CRYSTAL induced robust tumor regression in advanced murine and rabbit models, remodeled immunosuppressive environments, and promoted host STING-dependent CD8(+) T cell priming. CRYSTAL activated interferon responses in human head and neck squamous cell carcinoma biopsies, underscoring its translational potential for cancer immunotherapy.
Author Info:
1Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA.
2Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
3Department of Chemical En
gineering, University of Michigan, Ann Arbor, MI, USA.
4Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, MI, USA.
5Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
6Department of Microbiology, Genetics, and Immunology, Michigan State University, East Lansing, MI, USA.
7Department of Small Animal Clinical Sciences, Michigan State University, East Lansing, MI, USA.
8Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA.
9Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
10Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
#Contributed equally.
Citation: Science 2026 May 7 392:eadx1893 Epub05/07/2026
