Sensitive target living cell surfaces. Such a

Sensitive and specific detection of cancer
cells serves a crucial role in
the prevention, effective treatment, and examination of cancer metastasis 1, 2. Nowadays, the most common techniques in molecular biology for
detecting cancer cells are immunophenotyping by flow cytometry or antibody
microarray, identification of cancer-specific (epi)genetic mutations by PCRs
and sequencing, and analysis of the transcriptome by DNA microarrays and
RNA-seq technologies 3. In particular,
immunophenotyping technologies due to the analysis of cell-surface biomarkers
without labor-intensive sample pretreatments have
become more popular in recent years. However, employing different labeled
antibodies, which require expensive
equipment and lack an appropriate
signal amplification strategy for improving the sensitivity, has limited their
applications in diagnosis 3-7.

            The emergence of nucleic acid nanotechnology, based on the
programmability of Watson-Crick base-pairing, has made DNA as a widely used
building block for the assembly of nanoscale addressable materials and dynamic
molecular architectures 8, 9. Such biomimetic molecular devices in a wide
range of size and function, are
characterized by such features as sequence programmability, evident
biocompatibility, chemical addressability, and exceptional
biostability. These nanoassemblies can autonomously move or process
information and combine with different functional elements such as aptamers – artificial
nucleic acids with binding capability
to particular targets. Aptamer moieties can guide the intended nanodevices to
target cell surfaces and provide a distinguished platform for in situ
construction with accurate spatial control of
nanofactories on target living cell surfaces. Such a platform can be utilized for smart functions such as sensing,
computation, signal amplification or
manipulation of biological activities 9-15.

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Signal amplification, the capability of
increasing the signal intensity to an acceptable level, is a ubiquitous feature
in biology and engineering 16-18. Nanomaterial-based signal amplifications have attracted much
attention due to their rapid analysis procedures and easy miniaturization 19-21. In these strategies, the nanomaterials
usually serve as catalysts to trigger the detectable signals in which the
interaction of the reporter and the target lead to a multitude of reporter
molecules (catalysis) or carriers/loaders for signal tags (multivalency) 21, 22. Among the nanomaterial building blocks, DNA
– as a natural bridge between nanotechnology and biotechnology with
exceptional properties – provides a generic material for nanoscale engineering
and enzyme-free signal amplifications 23. The improvements in this subfield have
resulted in the design of simple and logical ultrasensitive sensing
platforms through the construction of structural
bulk-scale nanoassemblies, such as linear
and branched nanostructures, DNA origamis,
DNA hydrogels, and DNA multi-arms 8, 24-26.

As a result, numerous aptamer-integrated DNA nanostructures have recently been proposed for cancer imaging and detection 13, 27-29. For example, Kelley and coworkers
designed a self-assembled quantum dot DNA hydrogels
for xenografted breast cancer tracing 30. Using
DNA hydrogel formation technology, Zuo and coworkers proposed a strategy
in which porous DNA
hydrogels serve as cloaking networks of circulating tumor cells for subsequent
culture and analysis  31. Douglas et al designed an
autonomous aptamer-guided DNA nanorobot capable of sensing and releasing of
molecular payloads to tumor cells32.

In order to convert the aptamer-target binding events into color signals, numerous
sensitive non-apparatus detection approaches have been reported 33-35. Colorimetric assays, particularly those exploiting G-quadruplex
DNAzymes with peroxidase activity as signal-amplifying elements have been used in the detection of cancer
cells, due to simplicity in design, robustness across diverse conditions, and
cost-effectiveness 33, 36, 37. Using this signal
amplifier and other relatives like split G-quadruplex partzymes, Shi and
coworkers developed a colorimetric aptasensor for the detection of  human leukemic lymphoblast (CCRF-CEM cells) 36. Furthermore, the Li group proposed a label-free aptamer-based
strategy and a G-quadruplex sequence as the signal probe to detect the same cancer
cells 37. To improve the sensitivity of G-quadruplex DNAzyme-based sensors,
various strategies such as rolling
circle amplification (RCA) 38, polymerase chain reaction (PCR) 39, autonomous DNA machine 40  and strand displacement
amplification (SDA) 41 have been employed. However,
an ideal aptasensor which offers ultrasensitive colorimetric sensing platform for cancer cell detection is still in need of exploration.