Rheumatoid arthritis (RA) severely threatens human health by causing inflammation, swelling, and pain in the joints and resulting in persistent synovitis and irreversible joint disability. In the development of RA, pro-inflammatory M1 macrophages, which express high levels of reactive oxygen species (ROS) and nitric oxide (NO), induce synovial inflammation and bone erosion. Eliminating ROS and NO in the inflamed joints is a potential RA therapeutic approach, which can drive the transition of pro-inflammatory M1 macrophages to the anti-inflammatory M2 phenotype. Taking advantage of the intrinsic ROS- and NO-scavenging capability of DNA molecules, herein, we report the development of folic acid-modified triangular DNA origami nanostructures (FA-tDONs) for targeted RA treatment. FA-tDONs could efficiently scavenge ROS and NO and actively target M1 macrophages, facilitating the M1-to-M2 transition and the recovery of associated cytokines and biomarkers to the normal level. The therapeutic efficacy of FA-tDONs was examined in the RA mouse model. As validated by appearance, histological, and serum examinations, FA-tDONs treatment effectively alleviated synovial infiltration and cartilage damage, attenuating disease progression. This study demonstrated the usage of DNA origami for RA treatment and suggested its potential in other antioxidant therapies.

Chemoimmunotherapy represents an attractive approach for cancer treatment, which requires a compatible co-delivery system to achieve the synergetic therapeutic effects. Among various nanocarriers, DNA nanostructures have recently been proposed as promising candidates for drug delivery system due to the excellent biocompatibility. Herein, we employ DNA tetrahedron to create a co-delivery nanoplatform that combines the chemotherapeutic drug doxorubicin and the immunotherapeutic agent CpG oligodeoxynucleotides. The DTN-CpG/DOX nanoparticles show synergistic therapeutic effects in terms of enhanced immunostimulatory activity and pronounced antitumor efficiency. The simultaneous loading drugs with modifiable DNA nanostructures represent an attractive strategy for facile delivery of various therapeutic components.

Triple-negative breast cancer (TNBC) is highly aggressive with a poor clinical prognosis and no targeted therapy. The c-Myc protein is a master transcription factor and a potential therapeutic target for TNBC. In this study, we develop a PROTAC (PROteolysis TArgeting Chimera) based on TNA (threose nucleic acid) and DNA that effectively targets and degrades c-Myc. The TNA aptamer is selected in vitro to bind the c-Myc/Max heterodimer and appended to the E-box DNA sequence to create a high-affinity, biologically stable bivalent binder. The TNA-E box-pomalidomide (TEP) conjugate specifically degrades endogenous c-Myc/Max, inhibits TNBC cell proliferation, and sensitizes TNBC cells to the cyclin-dependent kinase inhibitor palbociclib in vitro. In a mouse TNBC model, combination therapy with TEP and palbociclib potently suppresses tumor growth. This study offers a promising nucleic acid-based PROTAC modality for both chemical biology studies and therapeutic interventions of TNBC.

Exosomes are nanoscale membrane vesicles actively released by cells and play an important role in the diagnosis of cancer-related diseases. However, it is challenging to efficiently enrich exosomes from extracellular fluids. In this work, we used DNA nanostructures as “nanoweights” during centrifugation to facilitate the enrichment of cancerous exosomes in human serum. Two different DNA tetrahedral nanostructures (DTNs), each carrying a specific aptamer for exosome biomarker recognition, were incubated with clinical samples simultaneously. One DTN triggered the cross-linking of multiple target exosomes and, therefore, enabled low-speed and fast centrifugation for enrichment. The other DTN further narrowed down the target exosome subtype and initiated a hybridization chain reaction (HCR) for sensitive signal amplification. The method enabled the detection of 1.8 × 102 MCF-7-derived exosomes per microliter and 5.6 × 102 HepG2-derived exosomes per microliter, with 1000-fold higher sensitivity than conventional ELISA and 10-fold higher sensitivity than some recently reported fluorescence assays. Besides, the dual-aptamer system simultaneously recognized multiple surface proteins, eliminating the interference risk from free proteins. Thus, this easy-to-operate method can enrich exosomes with excellent specificity and sensitivity and therefore will be appealing in biomedical research and clinical diagnosis.

We report the use of a protein ligase to covalently ligate a protein to a peptide nucleic acid (PNA). The rapid ligation demands only an N-terminal GL dipeptide in target...