2. Academic Validation
  3. STING agonist delivery by tumour-penetrating PEG-lipid nanodiscs primes robust anticancer immunity

STING agonist delivery by tumour-penetrating PEG-lipid nanodiscs primes robust anticancer immunity

  • Nat Mater. 2022 Jun;21(6):710-720. doi: 10.1038/s41563-022-01251-z.
Eric L Dane 1,  Alexis Belessiotis-Richards 2 3 4,  Coralie Backlund 1,  Jianing Wang 5,  Kousuke Hidaka 6,  Lauren E Milling 1 7,  Sachin Bhagchandani 1 8,  Mariane B Melo 1,  Shengwei Wu 1,  Na Li 1,  Nathan Donahue 1,  Kaiyuan Ni 1,  Leyuan Ma 1,  Masanori Okaniwa 9,  Molly M Stevens 2 3 4,  Alfredo Alexander-Katz 10,  Darrell J Irvine 11 12 13 14 15
Affiliations

Affiliations

  • 1 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 2 Department of Materials, Imperial College London, London, UK.
  • 3 Department of Bioengineering, Imperial College London, London, UK.
  • 4 Institute of Biomedical Engineering, Imperial College London, London, UK.
  • 5 Millennium Pharmaceuticals, Inc., Cambridge, MA, USA.
  • 6 Immunology Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
  • 7 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 8 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 9 Oncology Drug Discovery Unit, Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
  • 10 Department of Materials Science & Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 11 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. djirvine@mit.edu.
  • 12 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. djirvine@mit.edu.
  • 13 Department of Materials Science & Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. djirvine@mit.edu.
  • 14 Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. djirvine@mit.edu.
  • 15 Howard Hughes Medical Institute, Chevy Chase, MD, USA. djirvine@mit.edu.
PMID: 35606429 DOI: 10.1038/s41563-022-01251-z
Abstract

Activation of the innate immune STimulator of INterferon Genes (STING) pathway potentiates antitumour immunity, but systemic delivery of STING agonists to tumours is challenging. We conjugated STING-activating cyclic dinucleotides (CDNs) to Pegylated Lipids (CDN-PEG-lipids; PEG, polyethylene glycol) via a Cleavable Linker and incorporated them into lipid nanodiscs (LNDs), which are discoid nanoparticles formed by self-assembly. Compared to state-of-the-art liposomes, intravenously administered LNDs carrying CDN-PEG-lipid (LND-CDNs) exhibited more efficient penetration of tumours, exposing the majority of tumour cells to STING agonist. A single dose of LND-CDNs induced rejection of established tumours, coincident with immune memory against tumour rechallenge. Although CDNs were not directly tumoricidal, LND-CDN uptake by Cancer cells correlated with robust T-cell activation by promoting CDN and tumour antigen co-localization in dendritic cells. LNDs thus appear promising as a vehicle for robust delivery of compounds throughout solid tumours, which can be exploited for enhanced immunotherapy.

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