posted on 2023-11-21, 18:40authored byMingming Lu, Yating Zhu, Dan Li, Zhifang Zhou, Han Lin, Haofei Hong, Jie Shi, Zhimeng Wu
Shiga
toxin (Stx) is associated with foodborne infections of some Shigella spp. and Shiga toxin-producing Escherichia
coli (STEC), leading to life-threatening hemolytic
uremic syndrome (HUS). Target-specific therapeutics against HUS are
currently unavailable in clinical practice. Herein, we reported the
construction and in vitro characterization of Gb3-coated
bovine milk exosomes (Gb3-mExo) as a multivalent Shiga toxin neutralizer,
utilizing the natural advantages of milk exosomes (mExo) in drug delivery
and multivalent interactions between Stx and its receptor Gb3. Gb3-mExo
constructs were achieved by conjugating mExo with the Gb3 derivatives
containing stearic acid-derived lipid tail, which was prepared through
an efficient chemoenzymatic approach. The constructs were able to
potently neutralize the binding of the B subunit of Stx2 (Stx2B) to
receptor Gb3 immobilized on the plate or expressed on model cells.
General safety of the constructs was evidenced by the cytotoxicity
analysis and hemolysis assay. In addition to the excellent stability
under conventional storage and handling conditions, the construct
can also retain most of its neutralization potency under gastrointestinal
pH extremes, showing the potential for oral administration. Considering
the natural availability and excellent biocompatibility of mExo, Gb3-mExo
conjugates should prove to be a practical prophylactic and therapeutic
for the Shiga toxin-related infections.