Investigation of the Relationship between Aptamers’ Targeting Functions and Human Plasma Proteins

适体 微尺度热泳 核仁素 生物 计算生物学 化学 细胞生物学 生物化学 分子生物学 核仁 细胞质
作者
Jia Liu,Zhiqiang Ren,Yang Sun,Liujun Xu,Dali Wei,Weihong Tan,Ding Ding
出处
期刊:ACS Nano [American Chemical Society]
卷期号:17 (23): 24329-24342 被引量:1
标识
DOI:10.1021/acsnano.3c10238
摘要

Aptamers are single-stranded DNA or RNA molecules capable of recognizing targets via specific three-dimensional structures. Taking advantage of this unique targeting function, aptamers have been extensively applied to bioanalysis and disease theranostics. However, the targeting functionality of aptamers in the physiological milieu is greatly impeded compared with their in vitro applications. To investigate the physiological factors that adversely affect the in vivo targeting ability of aptamers, we herein systematically studied the interactions between human plasma proteins and aptamers and the specific effects of plasma proteins on aptamer targeting. Microscale thermophoresis and flow cytometry analysis showed that plasma interacted with aptamers, restricting their affinity toward targeted tumor cells. Further pull-down assay and proteomic identification verified that the interactions between aptamers and plasma proteins were mainly involved in complement activation and immune response as well as showed structure-selective and sequence-specific features. Particularly, the fibronectin 1 (FN1) protein showed dramatically specific interactions with nucleolin (NCL) targeting aptamer AS1411. The competitive binding between FN1 and NCL almost deprived the AS1411 aptamer's targeting ability in vivo. In order to maintain the targeting function in the physiological milieu, a series of optimizations were performed via the chemical modifications of AS1411 aptamer, and 3′-terminal pegylation was demonstrated to be resistant to the interaction with FN1, leading to improved tumor-targeting effects. This work emphasizes the physiological environment influences on aptamers targeting functionality and suggests that rational design and modification of aptamers to minimize the nonspecific interaction with plasma proteins might be effective to maintain aptamer functionality in future clinical uses.
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