PDF(Pubmed)
Abstract：
Systemic infections caused by life-threatening pathogens represent one of the main factors leading to clinical death. In this study, we developed a pathogen infection-responsive and macrophage endoplasmic reticulum-targeting nanoplatform to alleviate systemic infections. The nanoplatform is composed of large-pore mesoporous silica nanoparticles (MSNs) grafted by an endoplasmic reticulum-targeting peptide, and a pathogen infection-responsive cap containing the reactive oxygen species-cleavable boronobenzyl acid linker and bovine serum albumin. The capped MSNs exhibited the capacity to high-efficiently load the antimicrobial peptide melittin, and to rapidly release the cargo triggered by H2O2 or the pathogen-macrophage interaction system, but had no obvious toxicity to macrophages. During the interaction with pathogenic Candida albicans cells and macrophages, the melittin-loading nanoplatform MSNE+MEL+TPB strongly inhibited pathogen growth, survived macrophages, and suppressed endoplasmic reticulum stress together with pro-inflammatory cytokine secretion. In a systemic infection model, the nanoplatform efficiently prevented kidney dysfunction, alleviated inflammatory symptoms, and protected the mice from death. This study developed a macrophage organelle-targeting nanoplatform for treatment of life-threatening systemic infections.
UNASSIGNED: Supplementary material (N2 adsorption curves of the initial synthesized MSNs, FT-IR spectra of MSN, and MSNE, MEL release from the FITC-MEL-loading MSNE + TPB induced by different concentration of H2O2, viability of NIH3T3 cells, and DC2.4 cells after treatment of free MEL or the used nanoparticles, effect of MEL on C. albicans growth and macrophage death during the interaction between C. albicans and macrophages, effect of MEL and the nanoparticles on S. aureus growth and macrophage death during the interaction between S. aureus and macrophages, quantification of GRP78 (a) and activated Caspase-3, flow cytometry analysis of kidney non-macrophages with the Alexa Fluor 594 signal, survival curve of the infected mice treated by MEL or MSNE + MEL, kidney burden, blood urea levels and serum TNF-α levels in the infected mice) is available in the online version of this article at 10.1007/s12274-022-4211-z.
UNASSIGNED: Supplementary material (N2 adsorption curves of the initial synthesized MSNs, FT-IR spectra of MSN, and MSNE, MEL release from the FITC-MEL-loading MSNE + TPB induced by different concentration of H2O2, viability of NIH3T3 cells, and DC2.4 cells after treatment of free MEL or the used nanoparticles, effect of MEL on C. albicans growth and macrophage death during the interaction between C. albicans and macrophages, effect of MEL and the nanoparticles on S. aureus growth and macrophage death during the interaction between S. aureus and macrophages, quantification of GRP78 (a) and activated Caspase-3, flow cytometry analysis of kidney non-macrophages with the Alexa Fluor 594 signal, survival curve of the infected mice treated by MEL or MSNE + MEL, kidney burden, blood urea levels and serum TNF-α levels in the infected mice) is available in the online version of this article at 10.1007/s12274-022-4211-z.
摘要：
由威胁生命的病原体引起的全身感染是导致临床死亡的主要因素之一。在这项研究中,我们开发了一种对病原体感染敏感的巨噬细胞内质网靶向纳米平台,以缓解全身感染.纳米平台由内质网靶向肽接枝的大孔介孔二氧化硅纳米颗粒（MSN）组成，和包含活性氧可裂解的硼苄基酸接头和牛血清白蛋白的病原体感染响应帽。加帽的MSN表现出高效负载抗菌肽蜂毒素的能力，并快速释放由H2O2或病原体-巨噬细胞相互作用系统触发的货物，但对巨噬细胞无明显毒性。在与致病性白色念珠菌细胞和巨噬细胞的相互作用，melittin负载纳米平台MSNE+MEL+TPB强烈抑制病原体生长，存活的巨噬细胞，并抑制内质网应激和促炎细胞因子的分泌。在全身感染模型中,纳米平台有效地预防了肾功能障碍，减轻炎症症状，保护老鼠免于死亡.这项研究开发了一种针对巨噬细胞细胞器的纳米平台，用于治疗危及生命的全身性感染。
UNASSIGNED：补充材料（初始合成MSNs的N2吸附曲线，MSN的FT-IR光谱,和MSNE,不同浓度H2O2诱导的负载FITC-MEL的MSNE+TPB释放MEL,NIH3T3细胞活力,和DC2.4细胞处理后的游离MEL或使用的纳米颗粒，在白色念珠菌与巨噬细胞相互作用过程中，MEL对白色念珠菌生长和巨噬细胞死亡的影响，MEL和纳米颗粒对金黄色葡萄球菌生长和巨噬细胞死亡的作用，在金黄色葡萄球菌和巨噬细胞之间的相互作用，GRP78（a）和激活的Caspase-3的定量，用AlexaFluor594信号对肾脏非巨噬细胞进行流式细胞术分析，用MEL或MSNE+MEL处理的感染小鼠的存活曲线，肾脏负担，感染小鼠的血液尿素水平和血清TNF-α水平）可在本文的在线版本中获得，网址为10.1007/s12274-022-4211-z。
UNASSIGNED：补充材料（初始合成MSNs的N2吸附曲线，
