Pathogen Infection-Responsive Nanoplatform Targeting Macrophage Endoplasmic Reticulum for Alleviating Sepsis

Pathogen-induced sepsis represents the main cause of infection-related death, and is becoming a great threat to human health. In this study, we developed a pathogen infection-responsive and macrophage endoplasmic reticulum-targeting nanoplatform to alleviate sepsis. The nanoplatform is composed of large-pore mesoporous silica nanoparticles (MSNs) grafted by an endoplasmic reticulum-targeting peptide (ERP), and a pathogen infection-responsive cap (TPB) containing the reactive oxygen species (ROS)-cleavable boronobenzyl acid linker (TSPBA) and bovine serum albumin (BSA). The TPB-capped MSNs exhibited the capacity to highly load the antimicrobial peptide melittin (MEL), and to rapidly release the cargo triggered by H2O2 or the pathogen-macrophage interaction system. During the interaction between pathogenic C. albicans cells and macrophages, the MEL-loading nanoplatform MSNE+MEL+TPB strongly inhibited pathogen growth, survived macrophages, and suppressed endoplasmic reticulum stress and secretion of pro-inflammatory cytokines. In a systemic infection model, the nanoplatform efficiently protected the mice from death, prevented kidney dysfunction and alleviated sepsis symptoms. This study developed an efficient multifunctional nanoplatform for treatment of sepsis. Funding Information: This work was supported by National Natural Science Foundation of China (3217010793, 31870139), Natural Science Foundation of Tianjin (19JCZDJC33800), and Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project (TSBICIP-KJGG-006). Declaration of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethics Approval Statement: All animal experiments were approved by the Animal Care and Use Committee at Nankai University.