摘要
Oligonucleotide therapeutics have great potential to target the currently undruggable genes and to generate entirely new therapeutic paradigms in multiple types of disease,thus having attracted much attention in recent years.However,their applications are greatly hindered by a lack of safe and efficient oligonucleotide-delivery vectors.Polyplex nanovesicles formed from oligonucleotides and the cationic block have shown exceptional features for the delivery of therapeutic oligonucleotides and other biopharmaceuticals.Nevertheless,these polyplex nanovesicles are deeply fraught with difficulty in tolerating physiological ionic strength.Inspired by the high binding ability between the dipicolylamine(DPA)/zinc(Ⅱ)complex and the phosphodiester moieties of oligonucleotides,herein,we designed a coordinative cationic block to solve the intrinsic stability dilemma.Moreover,we found the stability of the resulted polyplex nanovesicles could be easily tuned by the content of coordinated zinc ions.In vitro cellular studies implied that the prepared zinc(Ⅱ)-coordinative polyplex nanovesicles preferred to retain in the lysosomes upon internalization,making them ideal delivery candidates for the lysosome-targeting oligonucleotide therapeutics.
基金
financially supported by the National Key Research and Development Program of China (No.2021YFA1201200)
the National Natural Science Foundation of China (Nos. 51833008, 52173141 and 82102192)
Zhejiang Provincial Key Research and Development Program (No.2020C01123)
China Postdoctoral Science Foundation (No.2019M662059)
