Senescence-modulating nanoparticles SELECT the right senescent cells to treat fibrosis and cancer.

Abstract

Cellular senescence contributes dynamically to fibrosis and cancer depending on the senescent cell type and its tissue remodeling senescence-associated secretory phenotype; however, current senotherapies lack specificity in targeting pathogenic senescent cells and have limiting toxicities. In a recent issue of Science, Hinterleitner and colleagues designed P-selectin-directed nanoparticles (SMNPs) capable of delivering senotherapies specifically to pathogenic P-selectin+ senescent macrophages in fibrotic tissues while preventing uptake in beneficial senescent endothelial cells. Precision targeting by SMNPs resolved fibrosis and restored organ function in the lung and liver and minimized senotherapeutic toxicity in mice. In tumor models, SMNP targeting of this small senescent macrophage subset was sufficient to overcome fibrosis-mediated immune exclusion and sensitize liver and lung cancers to T cell-directed immunotherapy. P-selectin+ macrophages with senescent features were also enriched in fibrotic human tissues and treatment-refractory cancer patient samples. Overall, this study provides a platform for reducing the toxicity and enhancing the specificity of senotherapies necessary to advance their clinical development for treating chronic disease.