Spatio-Temporal Controlled Gene-Chemo Drug Delivery in a DNA Nanocomplex to Overcome Multidrug Resistance of Cancer Cells

Abstract

Multidrug resistance (MDR) in cancer cells is a substantial limitation to the success of chemotherapy. The spatio-temporal controlled gene-chemo therapeutics strategy is expected to surmount the limitation of MDR. We herein develop a DNA nanocomplex to achieve intrinsic stimuli-responsive spatio-temporal controlled gene-chemo drug delivery, overcoming MDR of cancer cells. The drug delivery system consisted of a restriction endonuclease (HhaI)-degradable DNA hydrogel layer, an acid-responsive HhaI nanocapsule (HhaI-GDA), and a glutathione (GSH)-sensitive dendritic mesoporous organosilica nanoparticle (DMON). The DNA hydrogel layer consisted of a DNA network formed through interfacial assembly from ultralong single-stranded DNA (ssDNA), which contained multiple tandem repeated antisense oligonucleotides (ASOs). DMON had dendritic mesopores for enhanced loading of anti-tumor drug doxorubicin (DOX). Upon cellular uptake of the DNA nanocomplex, the GDA shell was degraded at a lysosomal microenvironment, and the activity of HhaI was activated, leading to accurate cleavage ultralong ssDNA to release ASO as gene drugs, which downregulated the expression of MDR-related P glycoprotein. Spatio-temporal sequentially, DMONs containing disulfide bonds responded to intracellular GSH to release DOX for enhanced chemotherapy.

DNA-Based Hydrogels with Multidrug Sequential Release for Promoting Diabetic Wound Regeneration

“…Agilegel is a 3D physically cross-linked DNA hydrogel composed of two DNA dendritic monomers, Y and L. Hierarchically structured DNA hydrogels provide three types of drug loading via covalent binding to DNA phosphate backbones, noncovalent binding to base pairs, and physical encapsulation of the advanced porous structure. Different physiochemical forces confer the ability to release drugs from Agilegel sequentially. − The drugs integrated into Agilegel here include the following: (1) AgNCs, as antibacterial agents, have proved to have superior antibacterial properties due to their ultrasmall size and highly efficient nanoreservoirs of Ag atoms. , Compared to Ag ions, AgNCs can sustainably release Ag atoms and avoid the Ag ion pulse, which can significantly reduce their in vivo cytotoxicity. , AgNCs are synthesized in situ by using the cytosine-rich Y-shaped DNA monomer as a template. The programmable DNA template can precisely control the spatial structure of AgNCs and prevent them from aggregating, which enables AgNCs to maintain their antibacterial activity for much longer than Ag nanoparticles .…”

Polymeric DNA Hydrogels and Their Applications in Drug Delivery for Cancer Therapy

“…The gene-photothermal synergistic therapy strategy facilitated the development of DNAzyme-based gene therapy. Yao et al recently developed a DNA hybrid nanogel (DMON/DOX-DNA/ASO-HhaI@GDA) for the chemo and gene cooperative therapy [ 58 ]. The DOX/gene delivery system consisted of an acid-responsive Hhal degradable hydrogel layer (Hhal@GDA) and a GSH-sensitive dendritic mesoporous organosilica nanoparticle (DMON).…”

Progress in Programmable DNA-Aided Self-Assembly of the Master Frame of a Drug Delivery System

“…The nanocomplex DDS could be used for targeted delivery of peptide drug to tumor cells, and the drug release can be activated by irradiation stimuli. Zhao and Yang et al 141 recently developed a DNA nanocomplex as the MF of a DDS. It can deliver both chemotherapeutics and gene drugs to overcome the MDR of tumor cells, and the stimuli-responsive delivery can be controlled spatiotemporally (Figure 17b).…”

“…(b) A nanocomplex based on DNA nanogel to be the MF of a DDS. Reproduced with permission from ref . Copyright 2022 American Chemical Society.…”