CD44‐Targeting Drug Delivery System of Exosomes Loading Forsythiaside A Combats Liver Fibrosis via Regulating NLRP3‐Mediated Pyroptosis

Abstract Liver fibrosis is a progressive pathological process induced by various stimuli and may progress to liver cirrhosis and cancer. Forsythiaside A (FA) is an active ingredient extracted from traditional Chinese medicine Forsythiae Fructus and has prominent hepatoprotective activities. However, the unsatisfactory pharmacokinetic properties restrict its clinical application. In this study, the nanocarrier of CD44‐specific ligand Hyaluronic acid (HA)‐modified milk‐derived exosomes (mExo) encapsulated with FA (HA‐mExo‐FA) is developed. As a result, HA modification could deliver drug‐loaded exosomes to the target cells and form a specific ligand‐receptor interaction with CD44, thus improving the anti‐liver fibrosis effect of FA. In vitro findings indicate that HA‐mExo‐FA could inhibit TGF‐ β 1‐induced LX2 cell proliferation, reduce α ‐SMA and collagen gene and protein levels, and promote the apoptosis of activated LX2 cells. In vivo results demonstrate that HA‐mExo‐FA could improve liver morphology and function changes in zebrafish larvae. The anti‐liver fibrosis mechanism of HA‐mExo‐FA may be attributed to the inhibition of NLRP3‐mediated pyroptosis. In addition, the effect of HA‐mExo‐FA on TAA‐induced increase in NLRP3 production is attenuated by NLRP3 inhibitor MCC950. Collectively, this study demonstrates the promising application of HA‐mExo‐FA in drug delivery with high specificity and provides a powerful and novel delivery platform for liver fibrosis therapy.