Dual-Responsive Nanogels with Cascaded Gentamicin Release and Lysosomal Escape to Combat Intracellular Small Colony Variants for Peritonitis and Sepsis Therapies.

Abstract

Intracellular bacteria are the major cause of serious infections including sepsis and peritonitis, but face great challenges in fighting against the stubborn intracellular small colony variants (SCVs). Herein, the authors have developed nanogels (NGs) to destroy both planktonic bacteria and SCVs and eliminate excessive inflammations for peritonitis and sepsis therapies. Free gentamicin (GEN) and hydroxyapatite nanoparticles (NPs) with GEN loading and mannose grafts (mHAG) are inoculated into ε-polylysine NGs to obtain NG@G1-mHAG2 through crosslinking with phenylboronic acid and tannic acid. The H2O2 consumption after reaction with phenylboronic esters and the elimination of free radicals by tannic acid alleviates the escalated inflammatory status to promote sepsis therapy. After mannose-mediated uptake into macrophages, the acid-triggered degradation of mHAG NPs generates Ca2+ to destabilize lysosomes and the efficient lysosomal escape leads to reversion of hypometabolic SCVs into normal phenotype and their sensitivity to GEN. In a peritonitis mouse model, NG@G1-mHAG2 treatment provides strong and persistent bactericidal effects against both extracellular bacteria and intracellular SCVs and extends survival of peritonitis mice without apparent hepatomegaly, splenomegaly, pulmonary edema, and inflammatory cell infiltration. Thus, this study demonstrates a concise and versatile strategy to eliminate SCVs and relieve inflammatory storms for peritonitis and sepsis therapies without infection recurrence.