NLRP3 inflammasome inhibitor(Exscientia/University of Oxford)

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.

Nucleotide-binding oligomerization domain like receptor protein 3 (NLRP3) inflammasome is considered as a critical contributor to pathological angiogenesis and neuronal dysfunction. However, its role in ischemic retinopathies remains unclear. In this study, we aimed to evaluate the role of NLRP3 inflammasome in ischemic retinopathies and the effects of the NLRP3 inflammasome inhibitor OLT1177 on retinal neovascularization (RNV) and neuronal dysfunction in a mouse model of oxygen induced retinopathy (OIR). A single-cell transcriptome analysis was performed using public data from the preretinal proliferative membranes in patients suffering from proliferative diabetic retinopathy (PDR), which was verified by immunofluorescence and western blot. The OIR mouse model was established, with OLT1177 being intravitreally injected on postnatal day 12. The effects of OLT1177 on RNV, neuronal loss and the activation of NLRP3 inflammasome were explored. Our results demonstrated that the NLRP3 inflammasome and associated inflammatory responses were observed within microglia in both the preretinal proliferative membranes of PDR patients and the retinas of OIR mice. OLT1177 attenuated pathological RNV at a concentration of 100 μM. Furthermore, OLT1177 reduced the neuronal loss and maintained the astrocytic framework in the non-perfusion areas of retinas. Microglial activation and NLRP3 inflammasome-associated microglial inflammation were alleviated in the OLT1177-treated mice. In conclusion, NLRP3 inflammasome activation and microglial inflammation occurred in ischemic retinopathies and the inhibitor OLT1177 was well-tolerated and beneficial in attenuating RNV and preventing neuronal death in the retinas of OIR mice, which indicated that OLT1177 might be a promising treatment option for ischemic retinopathies.