Programming DNA Nanoassemblies into Polyvalent Lysosomal Degraders for Potent Degradation of Pathogenic Membrane Proteins.

Lysosome-targeting chimera (LYTAC) shows great promise for protein-based therapeutics by targeted degradation of disease-associated membrane or extracellular proteins, yet its efficiency is constrained by the limited binding affinity between LYTAC reagents and designated proteins. Here, we established a programmable and multivalent LYTAC system by tandem assembly of DNA into a high-affinity protein degrader, a heterodimer aptamer nanostructure targeting both pathogenic membrane protein and lysosome-targeting receptor (insulin-like growth factor 2 receptor, IGF2R) with adjustable spatial distribution or organization pattern. The DNA-based multivalent LYTACs showed enhanced efficacy in removing immune-checkpoint protein programmable death-ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR2) in tumor cell membrane that respectively motivated a significant increase in T cell activity and a potent effect on cancer cell growth inhibition. With high programmability and versatility, this multivalent LYTAC system holds considerable promise for realizing protein therapeutics with enhanced activity.

Incorporation of a Multi-Valent Aptamer into Electrochemical Biosensors to Achieve an Improved Performance for Thrombin Analysis in Blood Serum.

The electrochemical aptamer-based (E-AB) biosensor usually has a long reaction time when detecting thrombin. This work reports the design of an E-AB biosensor with dual recognition sites to quickly detect thrombin. Specifically, two specific recognition sites of thrombin were used to design three aptamer sequences (TBA-15, TBA-29 and TBA-U), followed by fabrication of corresponding sensors. First, we tested these three types of biosensors in tris buffer solution, and found that the response time of the TBA-U sensor to the same concentration of thrombin was about 2 hours, which is shorter than TBA-15 and TBA-29 sensors. Then, we also did the same test in 50 % diluted serum with 500 nM thrombin. The response time of the TBA-U sensor was about 2 hours, which is still faster than the 3 hours of TBA-15 sensor and the 5.5 hours for TBA-29 sensor. In addition, in terms of dynamic range and specificity, TBA-U has good performance.