DNA Framework-Programmed Cell Capture via Topology-Engineered Receptor–Ligand Interactions

Abstract

Receptor−ligand interactions (RLIs) that play pivotal roles in living organisms are often depicted with the classic keys-and-locks model. Nevertheless, RLIs on the cell surface are generally highly complex and nonlinear, partially due to the noncontinuous and dynamic distribution of receptors on extracellular membranes. Here, we develop a tetrahedral DNA framework (TDF)-programmed approach to topologically engineer RLIs on the cell membrane, which enables active recruitment-binding of clustered receptors for high-affinity capture of circulating tumor cells (CTCs). The four vertices of a TDF afford orthogonal anchoring of ligands with spatial organization, based on which we synthesized n-simplexes harboring 1−3 aptamers targeting epithelial cell adhesion molecule (EpCAM) that are overexpressed on the membrane of tumor cells. The 2-simplex with three aptamers not only shows increased binding affinity (∼19-fold) but prevents endocytosis by cells. By using 2-simplex as the capture probe, we demonstrate the high-efficiency CTC capture, which is challenged in real clinical breast cancer patient samples. This TDFprogrammed platform thus provides a powerful means for studying RLIs in physiological settings and for cancer diagnosis.

Engineering a Second‐Order DNA Logic‐Gated Nanorobot to Sense and Release on Live Cell Membranes for Multiplexed Diagnosis and Synergistic Therapy

“…Interestingly, SA‐DTS showed no binding or internalization to the receptor‐negative MCF‐10A cell line (Figure 2 c). This could be attributed to the modification on vertex of three bulky and electronegative SAs which can inhibit unwanted cellular uptake, in accordance with a previous report [11b] . The flow cytometry results of DTS modified with different numbers of streptavidin also confirmed this tendency (Figure S5).…”

Bioinspired DNA Nanointerface with Anisotropic Aptamers for Accurate Capture of Circulating Tumor Cells

“…[39,41] Therefore, we first selected EpCAM aptamers as a representative to construct homo multivalent nanointerface which have been reported previously, other than the cocktail of different isotropic aptamer. [42] Hence, we also assembled and examined TDNs without aptamers, as well as TDNs conjugated with three EpCAM aptamers (TDN-3 EpCAM). As observed in confocal laser scanning microscopy (CLSM), the DNA nanosynapse showed firm membrane adhesion on MCF-7, SKBR-3, and MDA-MB-231 cell lines ( Figure 1C).…”

Nucleic Acids Analysis

“…In addition, the intrinsic low cost of TDFs meets well the low-cost requirement of biosensor design because the TDFs can be assembled with only four DNA strands [120][121][122]. More importantly, the FNAs facilitated patterning of biosensing interfaces can be integrated into various sensing devices such as microfluidic devices and paper-fluidic devices [123,124], expanding its applications in many important fields such as miniaturized biosensors and integrated biosensors.…”