Harnessing Telodendrimer Nanotraps in Nanogels for Systemic Immune Modulation in Sepsis Treatment

Sepsis is featured by uncontrolled life-threatening systemic inflammatory responses to infection and tissue damage. Spontaneous attenuation of a broad spectrum of septic molecules and cytokines is promising for effective sepsis treatment. We have developed a functionalized nanosized hydrogel, i.e., nanogel (NG), via a one-pot precipitation polymerization using biocompatible, biodegradable monomers/cross-linkers and versatile polymerizable functional telodendrimer (TD) nanotraps (NTs) for effective scavenging of septic molecules. The telodendrimer nanogel (TD-NG) has a spherical morphology with a homogeneous size distribution around 300 nm. TD-NG is stable in plasma and can be degraded in the presence of reducing agents, e.g., intracellular glutathione. The size-exclusive nanogel network and the polyethylene glycol (PEG) shell coating exclude the abundant serum proteins for selective and effective capture of septic molecules, e.g., lipopolysaccharide (LPS), tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6. PEGylated TD-NGs are nontoxic in cell culture with low immune cell uptake and biocompatible after iv injection with prolonged circulation time and majority elimination into feces via liver bile ducts. Systemic administration of TD-NG significantly inhibits LPS-induced NF-κB activation and cytokine production. PEGylated TD-NGs effectively attenuate inflammatory molecules in situ for effective immune modulation, which ameliorates tissue damage and improves the survival rate in severe sepsis mouse models induced by cecum ligation and puncture.