STING agonist delivery by tumour-penetrating PEG-lipid nanodiscs primes robust anticancer immunity PMID: 35606429

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
12. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
13. Department of Materials Science & Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA. [email protected].
14. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA. [email protected].
15. Howard Hughes Medical Institute, Chevy Chase, MD, USA. [email protected].

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.