Nuclear-targeted chimeric peptide nanorods to amplify innate anti-tumor immunity through localized DNA damage and STING activation

J Control Release. 2024 May:369:531-544. doi: 10.1016/j.jconrel.2024.04.008. Epub 2024 Apr 9.

Abstract

Stimulator of the interferon genes (STING) pathway is appealing but challenging to potentiate the innate anti-tumor immunity. In this work, nuclear-targeted chimeric peptide nanorods (designated as PFPD) are constructed to amplify innate immunity through localized DNA damage and STING activation. Among which, the chimeric peptide (PpIX-FFVLKPKKKRKV) is fabricated with photosensitizer and nucleus targeting peptide sequence, which can self-assemble into nanorods and load STING agonist of DMXAA. The uniform nanosize distribution and good stability of PFPD improve the sequential targeting delivery of drugs towards tumor cells and nuclei. Under light irradiation, PFPD produce a large amount of reactive oxygen species (ROS) to destroy nuclear DNA in situ, and the released cytosolic DNA fragment will efficiently activate innate anti-tumor immunity in combination with STING agonist. In vitro and in vivo results indicate the superior ability of PFPD to activate natural killer cells and T cells, thus efficiently eradicating lung metastatic tumor without inducing unwanted side effects. This work provides a sophisticated strategy for localized activation of innate immunity for systemic tumor treatment, which may inspire the rational design of nanomedicine for tumor precision therapy.

Keywords: Immunologic cell death; Innate immunity; Nuclear targeting; Photodynamic therapy; cGAS/STING pathway.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • DNA Damage*
  • Female
  • Humans
  • Immunity, Innate* / drug effects
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / immunology
  • Lung Neoplasms / therapy
  • Membrane Proteins*
  • Mice
  • Mice, Inbred BALB C
  • Nanotubes, Peptide / chemistry
  • Neoplasms / drug therapy
  • Neoplasms / immunology
  • Neoplasms / therapy
  • Peptides / administration & dosage
  • Peptides / chemistry
  • Photosensitizing Agents / administration & dosage
  • Photosensitizing Agents / pharmacology
  • Reactive Oxygen Species / metabolism

Substances

  • Membrane Proteins
  • Photosensitizing Agents
  • STING1 protein, human
  • Nanotubes, Peptide
  • Reactive Oxygen Species
  • Antineoplastic Agents
  • Peptides