Angiopep-2 Modified Exosomes Load Rifampicin with Potential for Treating Central Nervous System Tuberculosis

Abstract

Background Central nervous system tuberculosis (CNS-TB) is the most devastating form of extrapulmonary tuberculosis. Rifampin (RIF) is a first-line antimicrobial agent with potent bactericidal action. Nonetheless, the blood-brain barrier (BBB) limits the therapeutic effects on CNS-TB. Exosomes, however, can facilitate drug movements across the BBB. In addition, exosomes show high biocompatibility and drug-loading capacity. They can also be modified to increase drug delivery efficacy. In this study, we loaded RIF into exosomes and modified the exosomes with a brain-targeting peptide to improve BBB permeability of RIF; we named these exosomes ANG-Exo-RIF. Methods Exosomes were isolated from the culture medium of BMSCs by differential ultracentrifugation and loaded RIF by electroporation and modified ANG by chemical reaction. To characterize ANG-Exo-RIF, Western blot (WB), nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) were performed. Bend.3 cells were incubated with DiI labeled ANG-Exo-RIF and then fluorescent microscopy and flow cytometry were used to evaluate the targeting ability of ANG-Exo-RIF in vitro. Fluorescence imaging and frozen section were used to evaluate the targeting ability of ANG-Exo-RIF in vivo. MIC and MBC were determined through microplate alamar blue assay (MABA). Results A novel exosome-based nanoparticle was developed. Compared with untargeted exosomes, the targeted exosomes exhibited high targeting capacity and permeability in vitro and in vivo. The MIC and MBC of ANG-Exo-RIF were 0.25 μg/mL, which were sufficient to meet the clinical needs. Conclusion In summary, excellent targeting ability, high antitubercular activity and biocompatibility endow ANG-Exo-RIF with potential for use in future translation-aimed research and provide hope for an effective CNS-TB treatment.

Periodontal ligament stem cell-derived exosome-loaded Emodin mediated antimicrobial photodynamic therapy against cariogenic bacteria

“…Currently, the investigation of using Exos as a delivery system for antimicrobial agents is still in its preliminary phases. Li et al [ 45 ] investigated the antimicrobial potential of angiopep-2 modified exosomes load rifampicin (ANG-Exo-RIF) on Mycobacterium tuberculosis strain H37Rv. Their findings revealed that the MIC of RIF, Exo-RIF, and ANG-Exo-RIF was 0.25 μg/mL against the H37Rv strain, indicating that the encapsulation of rifampicin in exosomes did not affect its antibacterial properties.…”

Folic acid‐decorated astrocytes‐derived exosomes enhanced the effect of temozolomide against glioma

“…The isolated exos (50 μg/mL, total protein) were co‐incubated with the DSPE‐PEG 2000 ‐FA (50 μg/mL) for 30 min with shaking at 37°C to prepare Astro‐exo‐FA. TMZ was loaded into the Astro‐exo‐FA through electroporation to obtain TMZ@Astro‐exo‐FA, according to a previous study 24 . Thus, TMZ (200 μg) and exos (200 μg) were mixed with PBS to a final volume of 500 μL in an electroporation cuvette.…”

“…TMZ was loaded into the Astro-exo-FA through electroporation to obtain TMZ@Astro-exo-FA, according to a previous study. 24 Thus, TMZ (200 μg) and exos (200 μg) were mixed with PBS to a final volume of 500 μL in an electroporation cuvette.…”

Current landscape of exosomes in tuberculosis development, diagnosis, and treatment applications

“…Li et al. designed a novel BMSC-exosome-based nanoparticle, ANG-Exo-RIF, loaded with rifampicin and the brain-targeting peptide angiopep-2 ( 97 ). ANG-Exo-RIF exhibited high targeting ability and penetration, excellent anti-TB activity, and good biocompatibility, which is promising for CNS-TB treatment ( Figure 4 ).…”