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

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 down-regulated the expression of MDR-related P glycoprotein. Spatio-temporal sequentially, DMONs containing disulfide bonds responded to intracellular GSH to release DOX for enhanced chemotherapy.