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

Eric L Dane; Alexis Belessiotis-Richards; Coralie Backlund; Jianing Wang; Kousuke Hidaka; Lauren E Milling; Sachin Bhagchandani; Mariane B Melo; Shengwei Wu; Na Li; Nathan Donahue; Kaiyuan Ni; Leyuan Ma; Masanori Okaniwa; Molly M Stevens; Alfredo Alexander-Katz; Darrell J Irvine

doi:10.1038/s41563-022-01251-z

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. Epub 2022 May 23.

Authors

Eric L Dane¹, Alexis Belessiotis-Richards^{2

3

4}, Coralie Backlund¹, Jianing Wang⁵, Kousuke Hidaka⁶, Lauren E Milling^{1

7}, Sachin Bhagchandani^{1

8}, Mariane B Melo¹, Shengwei Wu¹, Na Li¹, Nathan Donahue¹, Kaiyuan Ni¹, Leyuan Ma¹, Masanori Okaniwa⁹, Molly M Stevens^{2

3

4}, Alfredo Alexander-Katz¹⁰, Darrell J Irvine^{11

12

13

14

15}

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.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Humans
Immunotherapy
Lipids
Membrane Proteins / metabolism
Membrane Proteins / pharmacology
Nanoparticles* / therapeutic use
Neoplasms* / drug therapy

Substances

Lipids
Membrane Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding