Functional Nucleic Acids-Engineered Bio-Barcode Nanoplatforms for Targeted Synergistic Therapy of Multidrug-Resistant Cancer

Abstract

Rational design of multifunctional nanomedicines has revolutionized the therapeutic efficacy of cancers. Herein, we have constructed the functional nucleic acids (FNAs)-engineered nanoplatforms based on the concept of a bio-barcode (BBC) for synergistic targeted therapy of multidrug-resistant (MDR) cancer. In this study, the platinum(IV) prodrug is synthesized to covalently link two kinds of FNAs at a rational ratio to fabricate threedimensional BBC-like DNA nanoscaffolds, accompanied by the one-pot encapsulation of ZnO nanoparticles (NPs) through electrostatic interaction. The multivalent AS1411 aptamers equipped in ZnO@BBCs facilitate specific and efficient endocytosis into MDR human lung adenocarcinoma cells (A549/DDP). In response to the intracellular environment of A549/DDP cells, such as the lysosome-acidic pH and overexpressed GSH, the ZnO NPs are degraded into Zn 2+ ions for generating reactive oxygen species (ROS), while the Pt(IV) prodrugs are reduced into Pt(II) active species by glutathione (GSH), followed by the release of therapeutic DNAzymes for chemotherapy and gene therapy. In particular, the designed system plays an important role in remodeling the intracellular environment to reverse cancer MDR. On the one hand, the depletion of GSH promotes the downregulation of glutathione peroxidase 4 (GPX4) for amplifying oxidative stress and increasing lipid peroxidation (LPO), resulting in the activation of ferroptosis. On the other hand, the silence of early growth response protein 1 (Egr-1) mRNA by Zn 2+ -dependent DNAzymes directly inhibits the proliferation and migration of MDR cells, which further suppresses the Pglycoprotein (P-gp)-mediated drug efflux. Thus, the proposed nanoplatforms show great promise for the development of versatile therapeutic tools and personalized nanomedicines for MDR cancers.

Synergistic Viro-chemoimmunotherapy in Breast Cancer Enabled by Bioengineered Immunostimulatory Exosomes and Dual-Targeted Coxsackievirus B3

“…The subsequent steps involved deparaffinization, rehydration of tumor sections, and staining with antibodies against CD8 (98941, Cell Signaling Technology) and F4/80 (70076, Cell Signaling Technology). Immunohistochemistry (IHC) was carried out using the MACH4 Universal HRP-Polymer Detection System (BRI4012H, Biocare Medical) and Gill II hematoxylin solution (GHS232, Sigma-Aldrich) as previously documented . Finally, digital images were obtained using the Aperio ScanScope AT (Digital slide scanner, Leica Biosystems Inc.), and quantification analysis was executed via NIH ImageJ (version 1.52p), with results presented as relative optical density.…”

“…The AS1411 aptamer is a nonimmunogenic and thermally stable DNA aptamer, comprising 26 guanine-rich nucleotides with a quadruplex structure . The AS1411 aptamer can serve not only as a detection tool to identify nucleolin, a cell surface protein that is overexpressed in many cancer cells, but also as a targeting agent on the surface of various drug delivery systems. , …”

Functional Nucleic Acid-Based Immunomodulation for T Cell-Mediated Cancer Therapy

“…Currently, FNAs have been artificially designed or modified to exhibit distinct functions, such as catalyzing chemical reactions (e.g., ribozymes and DNAzymes), , specific binding to target molecules (e.g., aptamers), , and regulating protein expression (e.g., small interfering RNA (siRNA), − microRNA (miRNA), , antisense oligonucleotide (ASO), , and clustered regularly interspaced short palindromic repeats (CRISPR) , ). Due to their superior features including easy synthesis, convenient modification, small size, good biocompatibility, and high programmability, FNAs have attracted significant interest in the field of cancer immunotherapy . For example, FNAs have been used to generate cancer vaccines , and immunoadjuvants, − which can enhance the ability of APCs to elicit T cell activation.…”

Dual-mode optical biosensor based on multi-functional DNA structures for detecting bioactive small molecules

“…In recent years, DNA-based materials have advanced rapidly because of their unique properties, such as high specificity and predictability, as well as good biocompatibility and programmability. 7–9 In particular, rolling circle amplification (RCA)-based DNA flowers (DFs) with a petal-like shape and three-dimensional porous structure have attracted a tremendous amount of attention due to their easy synthesis and functionalization. 10,11 In addition, DNAzymes with a specific nucleic acid sequence in conjunction with certain cofactors can mimic the function of native enzymes.…”