CD44-Targeted pH-Responsive Nanoenzyme-Liposome Complexes Co-Delivering Ceria Nanozymes and Cryptotanshinone To Alleviate Liver Fibrosis

Liver fibrosis, driven by unresolved inflammation and oxidative stress, lacks effective therapies. We developed hyaluronic acid (HA)-functionalized, pH-sensitive liposomes (HA-CeCPL) coencapsulating cryptotanshinone (CTS), an NLRP3 inflammasome inhibitor, and biomineralized ceria nanozymes (Ce-BSA) for synergistic liver fibrosis therapy. HA-CeCPL demonstrated pH-responsive payload release and preferential accumulation in fibrotic livers via CD44-mediated targeting of macrophages. <i>In vitro</i>, HA-CeCPL enhanced cellular uptake in macrophages, suppressed NLRP3 inflammasomes activation, and reduced IL-1β secretion. Meanwhile, the nanozyme-liposome complexs effectively scavenged reactive oxygen species (ROS), thus attenuating HSC activation, as evidenced by downregulation of α-smooth muscle actin. <i>In vivo</i>, HA-CeCPL exhibited superior hepatic targeting in CCl₄-induced fibrotic mice. It significantly ameliorated liver injury, restored liver function, reduced collagen deposition, and suppressed α-SMA expression. Furthermore, HA-CeCPL interfered with NLRP3 inflammasome signaling and pro-inflammatory cytokine cascades, breaking the inflammation-fibrosis cycle. These results demonstrate that the targeted dual-pathway strategy (simultaneously quenching ROS and blocking NLRP3 activation) synergistically resolves liver fibrosis, offering a promising nanotherapeutic approach.