Reprogramming cellular senescence of hepatic stellate cells to combat liver fibrosis by targeted nanodrugs

Abstract

Senescence of activated hepatic stellate cells (aHSCs) is thought to be a promising alternative for limiting hepatic fibrosis. However, uncontrollable accumulation and spread of senescence in neighboring hepatocytes lead to inflammation and steatosis, aggravating fibrosis and even promoting carcinogenesis. To harness senescence for fibrotic treatment, aHSCs-targeted poly (lactic-co-glycolic acid) (PLGA) nanoplatforms have been constructed to integrate senescent induction of aHSCs and senescent reprogramming. Owing to the CD44 aptamer modification, the nanoplatform specifically delivers senescent inducers and small interfering RNAs (siRNAs) that silence nuclear factor-kappa B (NF-κB) in aHSCs, thereby inducing senescence and simultaneously suppressing the production of senescence-associated secretory phenotypes (SASPs) in aHSCs. The senescence of aHSCs decreases their proliferation, and achieves permanent inactivation even upon repeated fibrotic stimulus. Meanwhile, the elimination of SASPs interrupts the vicious cycle of senescent aHSCs with surrounding hepatocytes to decrease senescent and inflammatory accumulation in liver tissues. In vitro and in vivo results confirmed the superior ability of the nanoplatform to inhibit liver fibrosis and control the spread of senescence. Our work provides a nanoplatform for specifically inducing senescence of aHSCs and reveals a promising senescence modulation strategy for the treatment of liver fibrosis.