In the assembly of DNA nanostructures, the specificity of Watson-Crick base pairing is used to control matter at the nanoscale. Using this technology for drug delivery is a promising route toward the magic bullet concept, as it would allow the realization of complex assemblies that co-localize drugs, targeting ligands and other functionalities in one nanostructure. Anthracyclines' mechanism of action in cancer therapy is to intercalate DNA, and since DNA nanotechnology allows for such a high degree of customization, we hypothesized that this would allow us to tune the DNA nanostructures for optimal delivery of the anthracycline doxorubicin (Dox) to human breast cancer cells. We have tested two DNA origami nanostructures on three different breast cancer cell lines (MDA-MB-231, MDA-MB-468, and MCF-7). The different nanostructures were designed to exhibit varying degrees of global twist, leading to different amounts of relaxation in the DNA double-helix structure. By tuning the nanostructure design we are able to (i) tune the encapsulation efficiency and the release rate of the drug and (ii) increase the cytotoxicity and lower the intracellular elimination rate when compared to free Dox. Enhanced apoptosis induced by the delivery system in breast cancer cells was investigated using flow cytometry. The findings indicate that DNA origami nanostructures represent an efficient delivery system for Dox, resulting in high degrees of internalization and increased induction of programmed cell death in breast cancer cells. In addition, by designing the structures to exhibit different degrees of twist, we are able to rationally control and tailor the drug release kinetics.

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Following ischemic stroke, brain‐resident activated microglia and peripherally infiltrated inflammatory cells create a complicated and overactivated brain immune microenvironment, which causes neuron death and dramatically hinders neurological functional recovery. Herein, an engineering CXCL12 biomimetic decoy‐integrated versatile immunosuppressive nanoparticle (VIN) for management of the overactivated brain immune microenvironment is reported. The shell of VIN (membrane of CXCR4 overexpressed mesenchymal stem cells), can not only improve the homing of nanoparticles to the cerebral ischemic lesions, but also efficiently adsorb and neutralize CXCL12 to cut off infiltration of peripheral‐neutrophils and mononuclear macrophages. The loaded A151 (cGAS inhibitor, telomerase repeat sequences) can inhibit cGAS‐STING pathway in microglia, leading to microglia polarization toward an anti‐inflammatory M2‐like phenotype. Interestingly, A151 can be efficiently loaded onto the polydopamine nanospheres (PDA, the core of VIN) through the bridge of Zn2+. In the inflammatory site, PDA is oxidized by reactive oxygen species (ROS), with the disappearance of Zn2+ complexation effect, and then A151 realizes a controlled release. In a model of rat ischemic stroke, VIN integrates inflammation tropism, peripherally inflammatory cells filtrate, brain‐resident activated microglia polarization, as well as, ROS scavenging, exerting outstanding therapeutic effects on ameliorating the mortality, reducing the infarct volume, and protecting neurogenic functions of neurons.

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DNA nanostructures prepared by self-assembly possess good stability, high biocompatibility, and low immunogenicity as drug delivery vehicles. In this work, DNA tetrahedron (TD) was constructed and modified with SL2B aptamer (S) and folic acid (F). TD possessed a small diameter (~6 nm) and entered into the nucleus quickly. SL2B aptamer can inhibit cancer cell growth by disturbing vascular endothelial growth factor/Notch signaling pathways. To explore the effect of SL2B number on colorectal cancer inhibition, SL2B multimers (dimer, trimer, and tetramer) were constructed by functionalization of TD with different numbers of SL2B. One SL2B per TD was the most efficient anticancer strategy and showed significantly better anticancer efficacy than SL2B, probably due to the enhanced stability of SL2B by TD. Doxorubicin (DOX) is a potent anticancer agent that can intercalate into DNA double strands. Results showed that TD could facilitate DOX entrance into the nucleus and the intracellular delivery of DOX was further enhanced by functionalization of SL2B and F. DOX-intercalated TD modified with two F and two S (DOX@TD-2F2S) could cause sufficient HT-29 cell inhibition at a much lower DOX concentration. In sum, DOX@TD-2F2S exhibited a synergic anticancer biological effect with chemotherapy and can be a promising strategy for treating colorectal cancer.

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