Synthetic hydrogel nanoparticles for sepsis therapy.

Sepsis is a life-threatening condition caused by the extreme release of inflammatory mediators into the blood in response to infection (e.g., bacterial infection, COVID-19), resulting in the dysfunction of multiple organs. Currently, there is no direct treatment for sepsis. Here we report an abiotic hydrogel nanoparticle (HNP) as a potential therapeutic agent for late-stage sepsis. The HNP captures and neutralizes all variants of histones, a major inflammatory mediator released during sepsis. The highly optimized HNP has high capacity and long-term circulation capability for the selective sequestration and neutralization of histones. Intravenous injection of the HNP protects mice against a lethal dose of histones through the inhibition of platelet aggregation and migration into the lungs. In vivo administration in murine sepsis model mice results in near complete survival. These results establish the potential for synthetic, nonbiological polymer hydrogel sequestrants as a new intervention strategy for sepsis therapy and adds to our understanding of the importance of histones to this condition.

Design of abiotic polymer ligand-decorated lipid nanoparticles for effective neutralization of target toxins in the blood.

Macromolecular toxins often induce inflammatory cytokine production, multiple-organ dysfunction, and cell death. Synthetic polymer ligands (PLs) prepared with several functional monomers have the potential of neutralizing target toxins after binding to them; therefore, they are of significant interest as abiotic antidotes. Although PLs show little toxin neutralization effect in the bloodstream because of immediate elimination from there, the toxin neutralization effect is significantly improved by the direct decoration of PLs onto lipid nanoparticles (PL-LNPs). However, this direct decoration decreases PL mobility, induces LNP aggregation after capturing the target, and decreases LNP blood circulation time. We designed novel PL-LNPs to improve PL mobility, inhibit the aggregation tendency after capturing the target, and increase LNP blood circulation time in order to achieve highly effective toxin neutralization in vivo. Specifically, LNPs were modified with PLs-conjugated polyethylene glycol (PEG), and additional PEG was used to modify the PL-decorated LNPs (PL-PEG-LNPs). Histones were used as target toxins, and N-isopropylacrylamide-based PLs were used for histone capture. PEGylation increased the plasma LNP level 24 h after intravenous injection by ∼90 times and inhibited LNP aggregation after histone capture. The dissociation constant (Kd) of PL-PEG-LNPs against histone was two times smaller compared to that of PL-LNPs. Although PL-LNPs inhibited histone-platelet interaction in the bloodstream, a large amount of histone-PL-LNP complexes accumulated in the lungs because of aggregation. However, PL-PEG-LNPs inhibited both histone-platelet interaction and histone accumulation in the lungs. Importantly, PL-PEG-LNP treatment increased the survival rate of histone-treated mice compared to PL-LNPs. These results provide a platform for the development of abiotic antidote nanoparticles in vivo.