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Peer-reviewedCC BY-NC-ND 4.0Materials Today Bio

Targeting histone methylation with ROS nanoparticles delivering PARPi prodrugs to amplify the stimulation of cGAS-STING for immunotherapy in ovarian cancer

  • Yi Sun1
  • Hongyao Li1
  • He Zhang1
  • Hanchen Zhang2
  • Chun Xu3,4
  • Bin Li1
  • Haihua Xiao5
  • Dan Zhao1
5 affiliations
  1. 1Department of Gynecology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
  2. 2Beijing National Laboratory for Molecular Sciences, Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China
  3. 3Faculty of Medicine and Health, Sydney Dental School, The University of Sydney, Sydney, NSW, 2006, Australia
  4. 4Charles Perkins Centre, The University of Sydney, Camperdown, NSW, 2006, Australia
  5. 5Suzhou Institute of Pharmaceutical Innovation, Soochow University, Suzhou Industrial Park, No. 218 Xinghu Street, Suzhou City, Jiangsu Province, 215218, China
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Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPi) has improved survival in ovarian cancer (OC), yet its efficacy is severely compromised by the restoration of homologous recombination repair and enhanced drug efflux. Here, we report a reactive oxygen species (ROS)-responsive nanoparticle (DP@NP) for the co-delivery of PARPi and DOT1L inhibitor (DOT1Li) to overcome these limitations through a dual-function mechanism. DP@NP can be triggered by ROS in cancer cells, whereupon the released PARPi induces DNA damage, while DOT1Li augments DNA damage accumulation by suppressing PARPi efflux and impairing DNA repair. This coordinated dual action promotes the accumulation of cytosolic double-stranded DNA, thereby robustly activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. In vivo, DP@NP exhibits efficient tumor targeting and elicits pronounced antitumor activity across multiple OC models. Notably, it remodels the tumor immune microenvironment and upregulates PD-L1, thereby significantly enhancing tumor responsiveness to immune checkpoint inhibitors. This study presents a co-delivery strategy that enhances PARPi efficacy while concurrently promoting antitumor immune activation, offering a viable avenue for the treatment of OC.

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Cite

BibTeXRIS
BibTeX
@article{sun2026targeting,
  title = {{Targeting histone methylation with ROS nanoparticles delivering PARPi prodrugs to amplify the stimulation of cGAS-STING for immunotherapy in ovarian cancer}},
  author = {Yi Sun and Hongyao Li and He Zhang and Hanchen Zhang and Chun Xu and Bin Li and Haihua Xiao and Dan Zhao},
  journal = {Materials Today Bio},
  year = {2026},
  month = oct,
  doi = {10.1016/j.mtbio.2026.103777},
  url = {https://doi.org/10.1016/j.mtbio.2026.103777},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Targeting histone methylation with ROS nanoparticles delivering PARPi prodrugs to amplify the stimulation of cGAS-STING for immunotherapy in ovarian cancer
AU  - Yi Sun
AU  - Hongyao Li
AU  - He Zhang
AU  - Hanchen Zhang
AU  - Chun Xu
AU  - Bin Li
AU  - Haihua Xiao
AU  - Dan Zhao
PY  - 2026
DA  - 2026/10/23
JO  - Materials Today Bio
DO  - 10.1016/j.mtbio.2026.103777
UR  - https://doi.org/10.1016/j.mtbio.2026.103777
AB  - Poly(ADP-ribose) polymerase inhibitors (PARPi) has improved survival in ovarian cancer (OC), yet its efficacy is severely compromised by the restoration of homologous recombination repair and enhanced drug efflux. Here, we report a reactive oxygen species (ROS)-responsive nanoparticle (DP@NP) for the co-delivery of PARPi and DOT1L inhibitor (DOT1Li) to overcome these limitations through a dual-function mechanism. DP@NP can be triggered by ROS in cancer cells, whereupon the released PARPi induces DNA damage, while DOT1Li augments DNA damage accumulation by suppressing PARPi efflux and impairing DNA repair. This coordinated dual action promotes the accumulation of cytosolic double-stranded DNA, thereby robustly activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. In vivo, DP@NP exhibits efficient tumor targeting and elicits pronounced antitumor activity across multiple OC models. Notably, it remodels the tumor immune microenvironment and upregulates PD-L1, thereby significantly enhancing tumor responsiveness to immune checkpoint inhibitors. This study presents a co-delivery strategy that enhances PARPi efficacy while concurrently promoting antitumor immune activation, offering a viable avenue for the treatment of OC.
SN  - 2590-0064
ER  -