Liposomes can directly modulate serine hydrolase activity and lipid metabolism independent of cargo

Liposomes are lipid-based nanoparticles that can be used to encapsulate and deliver small molecules, biologics, nucleic acids and other cargo for improved solubility, targeting and controlled release in vivo. These widely studied and clinically validated nanocarriers are often assumed to be biologically inert, yet emerging studies point to important but understudied biological activity. Here, we utilized quantitative chemoproteomics to discover that PEGylated liposomes composed of saturated phospholipids and cholesterol can directly modulate lipase activity independent of their cargo. Macrophages treated with these empty liposomes under inflammatory states showed suppressed TNF-alpha secretion in a phospholipid headgroup- and cholesterol content-dependent manner. These findings reveal unexpected biological effects independent of drug cargo and provide a framework for assessing bioactivity of these common lipid nanocarriers using chemical biology approaches.