Enhanced Anti-inflammatory Activity of Peptide-Gold Nanoparticle Hybrids upon Cigarette Smoke Extract Modification through TLR Inhibition and Autophagy Induction

Overwhelming uncontrolled inflammation is the hallmark of pathophysiological features of many acute and chronic inflammatory diseases, such as sepsis and allergy and autoimmune disorders. It is important to develop potent pharmacological interventions to effectively control such detrimental inflammatory reactions in these diseases. Recently, we have developed a special class of peptide--gold nanoparticle hybrid system that can inhibit Toll-like receptor 4 (TLR4) signal transduction pathways and decrease its downstream inflammatory responses. Herein, we serendipitously discovered that a tiny amount of cigarette smoke extract (CSE, 1%) was able to significantly enhance the inhibitory activity of the hybrids on TLR4-mediated inflammatory responses. Mechanistically, it was found that active components in CSE were able to adsorb onto the hybrids and largely increased their cellular uptake in THP-1 cell-derived macrophages. Such high cellular uptake not only enhanced the inhibition on the endosomal acidification required for TLR4 activation but also contributed to autophagy induction and subsequent antioxidant protein expression. Consequently, this duel action strengthened the anti-inflammatory activity of the hybrids in cells and in an acute lung injury (ALI) mouse model. This work aids our fundamental understanding of nanoparticles regulating the innate immune responses. It also provides a new way to design potent anti-inflammatory nanotherapeutics for inflammatory diseases such as ALI.