Complement opsonized protein corona activated by precoated immunoglobulin enables neutrophil-hitchhiking for rapid and enhanced drug delivery for acute liver failure recovery

Abstract

In acute inflammation, the heightened activation and recruitment of immune cells present an opportunity to leverage them as natural carriers for efficient transport of diagnostic probes and nanotherapeutics. Although complement opsonization facilitates the internalization of nanomedicines by activated neutrophils, the development of strategies to specifically augment complement deposition remains a challenge. Herein, we engineer silymarin-loaded liposomes (Lips) coated with immunoglobulin G (IgG) to enhance complement 3 (C3) deposition in the protein corona, thereby enabling neutrophil-mediated, precise targeting to the site of inflammation. Through the examination of various serum proteins, we discover that IgG adsorption, particularly with its Fc portion exposed, prominently promotes C3 enrichment in the protein corona, resulting in C3 cleavage into iC3b. This facilitates the uptake of C3-enriched Lips by activated neutrophils with elevated C3 receptor expression, thus improving the efficiency and specificity of nanomedicine delivery to inflammatory site. Following the formation of neutrophil extracellular traps, the released nanomedicine effectively mitigates hepatocyte damage by eliminating accumulated reactive oxygen species and inducing a shift in macrophage polarization towards the anti-inflammatory M2 phenotype. Our IgG-modified nanomedicine demonstrates significant therapeutic efficacy against acute liver failure by regulating the protein corona and hitchhiking neutrophils, offering a promising strategy for efficient and precise treatment of inflammation.