Nongenetic Reprogramming of the Ligand Specificity of Growth Factor Receptors by Bispecific DNA Aptamers

Abstract

The reprogramming of receptor-ligand interactions affords an opportunity to direct cells to respond to user-defined external cues. Although this has often been achieved via the genetic engineering of receptors, an alternative, nongenetic approach is highly demanded. In this article, we propose the design of oligonucleotide-based synthetic switches that feature the ability to reprogram the ligand specificity of the growth factor receptor. We demonstrated that our synthetic switches induced growth factor signaling via the formation of the dynamic complex with specific external cues that would otherwise not induce the signaling. This chemical approach may be applied to designing a new class of chemical tools that can control the activities of native cells and represent smart and safer regenerative drugs.

Emerging Applications of Nanotechnology for Controlling Cell‐Surface Receptor Clustering

“…Fore xample,t he Sando group developed an ongenetic approach to reprogram the ligand specificity of RTKs (Figure 4). [45] RTKs are cell surface receptors that regulate fundamental cellular activities,s uch as cell proliferation, migration, and differentiation. [46] Reprograming the ligand specificity of RTKs provided an opportunity to customize cellular signaling and direct cell behavior with external stimuli in au ser-defined manner.U sing ab i-specific DNA aptamer that consisted of an aptamer sequence for binding to the RTK, and another aptamer sequence for binding to the external cue (Platelet-derived growth factor, PDGF), it was found that RTKdimerization and activation could be induced by adding the external cue (PDGF).…”

“…[46] Reprograming the ligand specificity of RTKs provided an opportunity to customize cellular signaling and direct cell behavior with external stimuli in au ser-defined manner.U sing ab i-specific DNA aptamer that consisted of an aptamer sequence for binding to the RTK, and another aptamer sequence for binding to the external cue (Platelet-derived growth factor, PDGF), it was found that RTKdimerization and activation could be induced by adding the external cue (PDGF). [45] This concept could be further integrated with existing DNA-based logic circuits or protein-based molecular devices to develop smart and safe regenerative medicines that can induce cell activity upon the application of auser-defined external cue. [45] Figure 2.…”

“…[45] This concept could be further integrated with existing DNA-based logic circuits or protein-based molecular devices to develop smart and safe regenerative medicines that can induce cell activity upon the application of auser-defined external cue. [45] Figure 2. a) Diagram of ephrin-B1 nanopatternsf or tuning eph-B2 receptor clustering.…”

Engineering Cell‐Surface Receptors with DNA Nanotechnology for Cell Manipulation

“…In addition to mimicking natural ligand‐trigger receptor activation, RTKs could be engineered with designed DNA nanodevices to reprogram cells to respond to noncognate ligands with artificially promoted cell migration. The Sando group designed a DNA aptamer‐mediated reprogramming of the interaction partner of receptor tyrosine kinases (DRIPaR) strategy to “rewire” RTK‐mediated signaling (Figure B) . The proof‐of‐concept DRIPaR consisted of bispecific aptamers both of the c‐Met aptamer and of another aptamer that bound to different external bio‐macromolecular targets (e.g., PDGF and thrombin).…”

“…The Sando group de-signedaD NA aptamer-mediated reprogramming of the interaction partner of receptor tyrosine kinases (DRIPaR) strategy to "rewire" RTK-mediateds ignaling ( Figure 4B). [62] The proof-ofconcept DRIPaRc onsisted of bispecific aptamers both of the c-Met aptamer and of another aptamer that bound to different externalb io-macromolecular targets (e.g.,P DGFa nd thrombin). c-Met signaling and cell migration were therefore promoted by user-defined signals through the formationo ft ernary complexes between two bispecific aptamersa nd their ligands.…”