A lysosome-targeted DNA nanodevice selectively targets macrophages to attenuate tumours

Chang Cui, Kasturi Chakraborty, Xu Anna Tang, Kelly Q. Schoenfelt, Alexandria Hoffman, Ariane Blank, Blake McBeth, Natalie Pulliam, Catherine A. Reardon, Swati A. Kulkarni, Tomas Vaisar, Andrea Ballabio, Yamuna Krishnan, Lev Becker*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Activating CD8+ T cells by antigen cross-presentation is remarkably effective at eliminating tumours. Although this function is traditionally attributed to dendritic cells, tumour-associated macrophages (TAMs) can also cross-present antigens. TAMs are the most abundant tumour-infiltrating leukocyte. Yet, TAMs have not been leveraged to activate CD8+ T cells because mechanisms that modulate their ability to cross-present antigens are incompletely understood. Here we show that TAMs harbour hyperactive cysteine protease activity in their lysosomes, which impedes antigen cross-presentation, thereby preventing CD8+ T cell activation. We developed a DNA nanodevice (E64-DNA) that targets the lysosomes of TAMs in mice. E64-DNA inhibits the population of cysteine proteases that is present specifically inside the lysosomes of TAMs, improves their ability to cross-present antigens and attenuates tumour growth via CD8+ T cells. When combined with cyclophosphamide, E64-DNA showed sustained tumour regression in a triple-negative-breast-cancer model. Our studies demonstrate that DNA nanodevices can be targeted with organelle-level precision to reprogram macrophages and achieve immunomodulation in vivo.

Original languageEnglish (US)
Pages (from-to)1394-1402
Number of pages9
JournalNature nanotechnology
Volume16
Issue number12
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Bioengineering
  • Atomic and Molecular Physics, and Optics
  • Biomedical Engineering
  • Materials Science(all)
  • Condensed Matter Physics
  • Electrical and Electronic Engineering

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