Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer
Fibrotic remodeling of tissues and tumors establishes immune-suppressive microenvironments that drive organ dysfunction and, in cancer, limit responses to immunotherapy. Cells exhibiting features of cellular senescence are conserved drivers of fibrotic remodeling and thus represent therapeutic targets, yet senescent states are heterogeneous and can exert both beneficial and pathogenic effects, complicating therapeutic intervention. Here, we show that P-selectin is selectively expressed by subsets of senescent-like cells in fibrotic tissues and fibrotic tumor microenvironments. Leveraging fucoidan-based nanoparticles that bind P-selectin, we develop senescence-modulating nanoparticles (SMNPs) to selectively target these disease-associated cell states. SMNPs exhibit potent antifibrotic and immunomodulatory activity while markedly improving therapeutic index. Mechanistically, we identify a pathogenic, immune-suppressive macrophage population as a principal functional target of SMNPs in vivo. In fibrotic tumors, niche remodeling restores immune infiltration and sensitizes tumors to immune checkpoint-based therapies. More broadly, SMNPs establish a generalizable nanotherapeutic strategy for selectively targeting pathogenic senescent cell subsets across fibrotic disease and cancer.
Authors
- Hailey V. Goldberg (ORCID: https://orcid.org/0000-0002-4830-5626)
- Tuomas Tammela (ORCID: https://orcid.org/0000-0003-3675-6961)
- Clemens Hinterleitner (ORCID: https://orcid.org/0000-0003-2416-9399)
- Rui Gardner (ORCID: https://orcid.org/0000-0002-7270-5136)
- Almudena Chaves Perez (ORCID: https://orcid.org/0000-0002-2663-4672)
- Matthew Joseph Bott (ORCID: https://orcid.org/0000-0003-0523-4028)
- Daniel A. Heller (ORCID: https://orcid.org/0000-0002-6866-0000)
- Xiang Li (ORCID: https://orcid.org/0000-0001-7422-251X)
- Aveline A. Filliol (ORCID: https://orcid.org/0000-0002-1345-8147)
- Maria Skamagki (ORCID: https://orcid.org/0000-0003-0332-4521)
- Charles M. Rudin (ORCID: https://orcid.org/0000-0001-5204-3465)
- Paul Bernard Romesser (ORCID: https://orcid.org/0000-0001-8268-2903)
- Stephen B. Ruiz (ORCID: https://orcid.org/0000-0002-1634-9798)
- Domhnall McHugh (ORCID: https://orcid.org/0000-0002-0255-5873)
- Janelle Simon
- Xueqian Zhuang (ORCID: https://orcid.org/0000-0001-7012-3223)
- J D Watson (ORCID: https://orcid.org/0000-0003-0988-2583)
- Yu-Jui Ho
- Scott W. Lowe
- Gabriel Dessotti Barretto
- Ana Marie Perea
- Wei Luan
- Valentin J. A. Barthet
- Natasha Rekhtman
- Sara Flowers
- Logan R. Hillger (ORCID: https://orcid.org/0009-0006-3614-3160)
- Kristen C. Vogt
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Cornell University (US)
- Tri-Institutional PhD Program in Chemical Biology (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-03-04
- DOI
- https://doi.org/10.64898/2026.03.02.706451
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 0.00