2. Academic Validation
  3. Amplifying STING activation by cyclic dinucleotide-manganese particles for local and systemic cancer metalloimmunotherapy

Amplifying STING activation by cyclic dinucleotide-manganese particles for local and systemic cancer metalloimmunotherapy

  • Nat Nanotechnol. 2021 Nov;16(11):1260-1270. doi: 10.1038/s41565-021-00962-9.
Xiaoqi Sun 1 2,  Yu Zhang 1,  Jiaqian Li 3,  Kyung Soo Park 2 4,  Kai Han 1 2,  Xingwu Zhou 1 2,  Yao Xu 1 2,  Jutaek Nam 1 2 5,  Jin Xu 1 2,  Xiaoyue Shi 1 2,  Lei Wei 6,  Yu Leo Lei 3 7 8,  James J Moon 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA.
  • 2 Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA.
  • 3 Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI, USA.
  • 4 Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
  • 5 College of Pharmacy, Chonnam National University, Gwangju, Republic of Korea.
  • 6 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
  • 7 Department of Otolaryngology, University of Michigan, Ann Arbor, MI, USA.
  • 8 Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • 9 Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI, USA. moonjj@umich.edu.
  • 10 Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA. moonjj@umich.edu.
  • 11 Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA. moonjj@umich.edu.
  • 12 Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. moonjj@umich.edu.
PMID: 34594005 DOI: 10.1038/s41565-021-00962-9
Abstract

Nutritional metal ions play critical roles in many important immune processes. Hence, the effective modulation of metal ions may open up new forms of immunotherapy, termed as metalloimmunotherapy. Here, we demonstrate a prototype of Cancer metalloimmunotherapy using cyclic dinucleotide (CDN) stimulator of interferon genes (STING) agonists and Mn2+. We screened various metal ions and discovered specific metal ions augmented STING agonist activity, wherein Mn2+ promoted a 12- to 77-fold potentiation effect across the prevalent human STING haplotypes. Notably, Mn2+ coordinated with CDN STING agonists to self-assemble into a nanoparticle (CDN-Mn2+ particle, CMP) that effectively delivered STING agonists to immune cells. The CMP, administered either by local intratumoural or systemic intravenous injection, initiated robust anti-tumour immunity, achieving remarkable therapeutic efficacy with minute doses of STING agonists in multiple murine tumour models. Overall, the CMP offers a new platform for local and systemic Cancer treatments, and this work underscores the great potential of coordination nanomedicine for metalloimmunotherapy.

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