Rifampicin-Loaded Polyelectrolyte Complex Eliminates Intracellular Bacteria through Thiol-Mediated Cellular Uptake and Oxidative Stress Enhancement.

The poor accumulation of antibiotics in the cytoplasm leads to the poor eradication of intracellular bacteria. Herein, a polyelectrolyte complex (PECs@Rif) allowing direct cytosolic delivery of rifampicin (Rif) was developed for the treatment of intracellular infections by complexation of poly(α-lipoic acid) (pLA) and oligosaccharide (COS) in water and loading Rif. Due to the thiol-mediated cellular uptake, PECs@Rif delivered 3.9 times higher Rif into the cytoplasm than that of the free Rif during 8 h of incubation. After entering cells, PECs@Rif released Rif by dissociating pLA into dihydrolipoic acid (DHLA) in the presence of intracellular thioredoxin reductase (TrxR). Notably, DHLA could reduce endogenous Fe(III) to Fe(II) and provide a catalyst for the Fenton reaction to produce a large amount of reactive oxygen species (ROS), which would assist Rif in eradicating intracellular bacteria. In vitro assay showed that PECs@Rif reduced almost 2.8 orders of magnitude of intracellular bacteria, much higher than 0.7 orders of magnitude of free Rif. The bacteremia-bearing mouse models showed that PECs@Rif reduced bacterial levels in the liver, spleen, and kidney by 2.2, 3.7, and 2.3 orders of magnitude, respectively, much higher than free Rif in corresponding tissues. The direct cytosolic delivery in a thiol-mediated manner and enhanced oxidative stress proposed a feasible strategy for treating intracellular bacteria infection.