Encapsulation of MCC950 in Liposomes Decorated with Anti-Frizzled 1 Improves Drug Bioavailability and Effectiveness in Fatty Liver Disease

Inflammasome activation plays a crucial role in the progressionto more severe stages of non-alcoholic fatty liver disease (NAFLD),representing a promising therapeutic target. MCC950 is a small moleculeacting as a potent and specific inhibitor of the canonical and non-canonicalactivation of the NLRP3 inflammasome, but its short plasmatic half-lifelimits its use. Herein, we report, for the first time, the encapsulationof MCC950 in poly(ethylene glycol) (PEG) liposomes (LPs) that arespecifically functionalized with an antibody against Frizzled 1 (FZD1),a g-coupled protein involved in the WNT pathway and overexpressedon inflammasome-activated macrophages. MCC950, encapsulated into PEG-LPformulations conjugated with an anti-FZD1 antibody, inhibits the NLRP3inflammasome activation at concentrations 10 times lower than thatof the free drug in THP-1 cells. Luminescent carbon dots (CDs) werealso co-encapsulated with MCC950 in LPs to obtain optically traceablenanoformulations that have proved the enhanced ability of the targetedLPs to be internalized into THP-1 cells with respect to their nontargetedcounterparts. Our results suggest that MCC950 encapsulation into targetedLPs represents a valuable strategy to achieve reformulation of theNLRP3 inhibitor, able to significantly curtail the threshold of MCC950doses for inhibiting inflammasome activation, thus offering a newtherapeutic approach.