YAP‐Suppressive Nanodrug Crosslinked Self‐Immunoregulatory Polysaccharide Injectable Hydrogel for Attenuating Cardiac Fibrosis to Treat Myocardial Infarction

Abstract The cardiac fibrosis caused by excessive deposition of collagen and the fibro‐inflammatory cascade reaction severely impedes the cardiac regenerative efficiency after myocardial infarction (MI) so that the onefold treating target is far from satisfying therapeutic efficacy. Herein, a yes‐associated protein (YAP)‐suppressive nanodrug‐crosslinked self‐immunoregulatory polysaccharide injectable hydrogel is fabricated for the first time. To this end, cationic liposomes loading YAP inhibitor verteporfin (Lipo‐VP) is prepared and coated with oxidized fucoidan (OFu), a unique anti‐inflammation polysaccharide, to form anti‐fibrotic and immunoregulatory nanodrug (OFu‐Lipo‐VP). The coated fucoidan itself acts as a reactive oxygen species (ROS) scavenger and inflammation regulator, thus facilitating angiogenesis function by eliciting endogenous vascular endothelial growth factor secretion of macrophages. Then an injectable hydrogel (termed as OFu‐Lipo‐VP‐PGA) is formed through addition reaction between the aldehyde groups of OFu‐Lipo‐VP and the thiol groups of thiol‐modified poly(γ‐glutamic acid) (PGA‐SH), where the thiol groups can also aid in eliminating ROS. The acute MI models are established and the infarcted male rats are treated with this injectable OFu‐Lipo‐VP‐PGA hydrogel after MI. The outcomes at 28 days post‐surgery indicate efficient restoration of cardiac functions and attenuation of cardiac fibrosis. This study opens up a new possibility for MI treatment with immunoregulatory and antifibrotic injectable polysaccharide‐based hydrogel.