Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer

Abstract

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.