Endogenous Enzyme-Activatable Spherical Nucleic Acids for Spatiotemporally Controlled Signal Amplification Molecular Imaging and Combinational Tumor Therapy

Abstract

Due to the adjustable hybridization activity, antinuclease digestion stability, and superior endocytosis, spherical nucleic acids (SNAs) have been actively developed as probes for molecular imaging and the development of noninvasive diagnosis and image-guided surgery. However, since highly expressed biomarkers in tumors are not negligible in normal tissues, an inevitable background signal and the inability to precisely release probes at the chosen region remain a challenge for SNAs. Herein, we proposed a rationally designed, endogenous enzyme-activatable functional SNA (Ep-SNA) for spatiotemporally controlled signal amplification molecular imaging and combinational tumor therapy. The self-assembled amphiphilic polymer micelles (SM-ASO), which were obtained by a simple and rapid copper-free strain-promoted azide–alkyne cycloaddition click reaction between dibenzocyclooctyne-modified antisense oligonucleotide and azide-containing aliphatic polymer polylactic acid, were introduced as the core elements of Ep-SNA. This Ep-SNA was then constructed by connecting two apurinic/apyrimidinic (AP) site-containing trailing DNA hairpins, which could occur via a hybridization chain reaction in the presence of low-abundance survivin mRNA to SM-ASO through complementary base pairing. Notably, the AP site-containing trailing DNA hairpins also empowered the SNA with the feasibility of drug delivery. Once this constructed intelligent Ep-SNA nanoprobe was specifically cleaved by the highly expressed cytoplasmic human apurinic/apyrimidinic endonuclease 1 in tumor cells, three key elements (trailing DNA hairpins, antisense oligonucleotide, and doxorubicin) could be released to enable subsequent high-sensitivity survivin mRNA imaging and combinational cancer therapy (gene silencing and chemotherapy). This strategy shows great application prospects of SNAs as a precise platform for the integration of disease diagnosis and treatment and can contribute to basic biomedical research.

Spherical nucleic acids: emerging amplifiers for therapeutic nanoplatforms

“…Zhang constructed a polymer SNA structure with the SNA shell containing antisense oligonucleotides targeting MC1R and prodrug inhibitors of tyrosinase, which successfully reduced melanin production in melanoma cells. 46 Zheng developed a polymer SNA with antisense oligonucleotides and an amphiphilic self-assembling polymer as the core, 79 which efficiently loaded nanoprobes and Dox. After treatment, the quantitative average fluorescence intensity was calculated to be 1.51-fold higher than that of nontumoral sites.…”

“…Zheng engineered an endogenous APE1 enzyme-activated SNA nanosensor for spatiotemporal signal amplification molecular imaging and combined cancer therapy. 79 This intelligent Ep-SNA@Dox nanosensor, containing DNA hairpins with AP sites, ASOs, and Dox, can be specifically cleaved by APE1 in tumor cells, enabling high-sensitivity imaging of mRNA and drug release. In vitro and in vivo experiments demonstrated that this nanosensor not only possesses high-sensitivity imaging capability for target molecules but also enables precise drug release, offering a new approach to combined therapy.…”

Synergy of Target-Induced Magnetic Network and Single-Drop Chromogenic System for Ultrasensitive “All-in-Tube” Detection of miRNA in Whole Blood

“…To meet the urgent need for ultrasensitivity in miRNA detection strategies, researchers have developed various miRNA detection methods based on isothermal amplification technologies. − Thereinto, enzyme-free isothermal amplification strategies, such as hybridization chain reaction, strand displacement reaction, entropy-driven reaction, and catalytic hairpin assembly (CHA), , are easier to apply in biomolecular analysis. As a powerful DNA amplification technique, CHA can induce the binding of two DNA hairpins to produce a large quantity of double-stranded DNA structures through the catalytic action of a primer strand.…”

π–π Stacking Network-Based Supramolecular Peptide Nanoprobe for Visualization of the ICB-Enhanced Ferroptosis Process

“…9 Spherical nucleic acids (SNA) have been designed to be used in combination therapy with gene silencing and CDT while allowing visualization of tumor-associated survivin mRNA levels to provide feedback on the effectiveness of the therapy. 10 BP (black phosphorus)-based synergistic nanoprobes (BP/CD (carbon nanodots)/Au/Dox (doxorubicin)) not only enable the combined treatment of PTT/PDT (photodynamic therapy)/chemotherapy, but also provide feedback on specific targets in tumor tissue. 11 Notably, recent developments in oncology have highlighted the effectiveness of ferroptosis and immune checkpoint blockade (ICB).…”