CD44-Targeted pH-Responsive Nanoenzyme-Liposome Complexes Co-Delivering Ceria Nanozymes and Cryptotanshinone To
Kai Liu1,2,3, Yuxin Zhao1,2,3, Nini Luo4,5
1School of Pharmacy, College of Modern Traditional Chinese Medicine Industry, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, P. R. China.
Abstract:
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. In vitro, 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. In vivo, 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.
