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 H(2)O(2) 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. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material (N(2) 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 H(2)O(2), 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.