Advanced Materials Xi'an Jiaotong University Chen Xin/Zhang Yanmin develop smart spherical nucleic acids for synergistic tumor therapy

The iNature tumorigenesis environment, especially aberrantly overexpressed oncogenic microRNAs, plays a key role in various activities of tumor progression
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However, developing strategies to effectively utilize and manipulate these oncogenic microRNAs for tumor therapy remains a challenge
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On February 15, 2022, Xin Chen and Yanmin Zhang from Xi'an Jiaotong University published a paper entitled "Intelligent Gold Nanoparticle s with Oncogenic MicroRNA-dependent Activities to Manipulate Tumorigenic Environments for Synergistic Tumor Therapy" in Advanced Materials (IF=31) journal.
To address this challenge, the study prepared spherical nucleic acids with gold nanoparticles as the core and antisense oligonucleotides as the outer shell
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Cross-linked to the oligonucleotide shell is a doxorubicin-conjugated DNA sequence (DNA-DOX)
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The oligonucleotide shell is designed to capture overexpressed miR-21/miR-155 and suppress the expression of these oncogenic miRNAs in tumor cells after tumor accumulation to manipulate the genetic environment for accurate gene therapy
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This process further induces the aggregation of these SNAs, which not only generates photothermal agents for in situ on-demand photothermal therapy, but also enlarges the size of SNAs and improves the retention time of SNAs in tumors for sustained treatment
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The capture of relevant miRNAs simultaneously triggers the intracellular release of DNA-DOX from SNAs to deliver tumor-specific chemotherapy
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In conclusion, the results of this study show that the combined treatment strategy has good tumor inhibition effect and high survival rate of tumor-bearing mice, and is expected to become an effective tumor treatment method.

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MicroRNAs (MiRNAs) are short noncoding RNA molecules that regulate gene expression in diverse cellular processes
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It has been reported that some specific miRNAs, such as miR-21 and miR-155, are abnormally up-regulated in many types of tumor cells
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The upregulation of miRNAs is closely related to various features of the tumor microenvironment during tumor progression, such as tumor cell proliferation, differentiation and migration, and few studies have used antisense oligonucleotides to inhibit these overexpressed oncogene miRNAs in order to produce effective tumor therapy
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To provide more antisense oligonucleotides, various targeting nanocarriers have been explored
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However, even so, the efficacy of these antisense oligonucleotide-based genetic therapies is still insufficient for clinical application
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This may be due to low biostability and off-target effects of antisense oligonucleotides, as well as nonspecific uptake of nanocarriers by kidney/liver and their poor retention within tumors
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To enhance therapeutic efficacy, several strategies have been investigated to combine inhibition of oncogenic miRNAs with chemotherapy and/or photothermal therapy by developing tailored nanoparticle systems
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However, in addition to the common problem of poor tumor retention of nanomaterials, these strategies are often designed to activate antisense oligonucleotides for gene therapy and release antitumor drugs for chemotherapy through two distinct processes
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This is unavoidable because different mechanisms are used to load these different components into the nanoparticle system
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But this approach has the potential to spatially and/or temporally separate therapeutic activation, which would hinder synergistic effects
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In addition, conventional photothermal formulations that provide indiscriminate photothermal convection in tumor cells and healthy cells in/around tumor tissue may also cause unexpected side effects
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Therefore, it is very important to develop a smart nanocomplex that is inactive and harmless in healthy cells, and at the same time it only performs a single trigger response of gene therapy, chemotherapy and photothermal therapy in tumor cells for a long time, which is expected to achieve highly effective therapeutic effects , with negligible damage to normal tissues and/or organs
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In this study, two types of spherical nucleic acids (SNAs) were prepared using gold nanoparticles (AuNPs), which are expected to provide various therapeutic approaches, These include oncogenic miRNAs inhibition (controlling the genetic environment), oncogenic miRNAs-triggered drug release, and oncogenic miRNAs-dependent photothermal convection (using the genetic environment) for effective, accurate, and sustained tumor therapy
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In this study, AuNPs were used as tunable photothermal reagents, which enable selective photothermal properties after switching from a monodisperse state to an aggregated state
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Oligonucleotides act as inhibitors to inhibit the expression of oncogenic miRNAs through complementary pairing for gene therapy
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Furthermore, the modification of AuNPs also ensured that the aggregation of AuNPs only occurred in tumor cells treated with tumor-specific photothermal therapy due to the designed coupling between SNA1, SNA2DOX and miR-21 overexpressed in tumor cells
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Furthermore, DOX binds to the miR-155 complement on SNA2DOX, and once the particle encounters oncogenic miR-155, gene therapy and chemotherapy are simultaneously performed, providing synergistic oncogenic miRNA inhibition, chemotherapy, and photothermal therapy in one nanoparticle system
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In conclusion, the results of this study show that the combined treatment strategy has good tumor inhibition effect and high survival rate of tumor-bearing mice, and is expected to be an effective tumor treatment method
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Reference message: https://onlinelibrary.
wiley.
com/doi/10.
1002/adma.
202110219