Computational Design and In Vitro and In Vivo Characterization of an ApoE-Based Synthetic High-Density Lipoprotein for Sepsis Therapy

Introduction: Septic patients have low levels of high-density lipoproteins (HDLs), which is a risk factor. Replenishing HDLs with synthetic HDLs (sHDLs) has shown promise as a therapy for sepsis. This study aimed to develop a computational approach to design and test new types of sHDLs for sepsis treatment. Methods: We used a three-step computational approach to design sHDL nanoparticles based on the structure of HDLs and their binding to endotoxins. We tested the efficacy of these sHDLs in two sepsis mouse models—cecal ligation and puncture (CLP)-induced and P. aeruginosa-induced sepsis models—and assessed their impact on inflammatory signaling in cells. Results: We designed four sHDL nanoparticles: two based on the ApoA-I sequence (YGZL1 and YGZL2) and two based on the ApoE sequence (YGZL3 and YGZL4). We demonstrated that an ApoE-based sHDL nanoparticle, YGZL3, provides effective protection against CLP- and P. aeruginosa-induced sepsis. The sHDLs effectively suppressed inflammatory signaling in HEK-blue or RAW264 cells. Conclusions: Unlike earlier approaches, we developed a new approach that employs computational simulations to design a new type of sHDL based on HDL’s structure and function. We found that YGZL3, an ApoE sequence-based sHDL, provides effective protection against sepsis in two mouse models.