LAUSR

Intracellular bacteria in latent or dormant states tolerate high-dose antibiotics. Fighting against these opportunistic bacteria has been a long-standing challenge. Herein, we design a cascade-targeting drug delivery system (DDS) that can sequentially target macrophages and intracellular bacteria, exhibiting on-site drug delivery. The DDS is fabricated by encapsulating rifampicin (Rif) into mannose-decorated poly(α-N-acryloyl-phenylalanine)-block-poly(β-N-acryloyl-D-aminoalanine) nanoparticles, denoted as Rif@FAM NPs. The mannose units on Rif@FAM NPs guide the initial macrophage-specific uptake and intracellular accumulation. After the uptake, the detachment of mannose in acidic phagolysosome via Schiff base cleavage exposes the D-aminoalanine moieties, which subsequently steer the NPs to escape from lysosomes and target intracellular bacteria through peptidoglycan-specific binding, as evidenced by the in-situ/ex-situ co-localization using confocal, flow cytometry, and TEM. Through the on-site Rif delivery, Rif@FAM NPs show superior in vitro and in vivo elimination efficiency than the control groups of free Rif or the DDSs lacking the macrophages- or bacteria-targeting moieties. Furthermore, Rif@FAM NPs remodel the innate immune response of the infected macrophages by up-regulating the M1/M2 polarization, resulting in a reinforced antibacterial capacity. Therefore, this biocompatible DDS enabling macrophages and bacteria targeting in a cascade manner provides a new outlook for the therapy of intracellular pathogen infection. This article is protected by copyright. All rights reserved.