In Vivo Activation of T-Cell Proliferation by Regulating Cell Surface Receptor Clustering Using a pH-Driven Interlocked DNA Nano-Spring

Abstract

Activation of T-cell proliferation specifically in a tumor is crucial for reducing the autoimmune side effects of antitumor immunotherapy. Herein, we developed a pH-driven interlocked DNA nano-spring (iDNS) to stimulate T-cell activation in vivo in response to the low pH value in a tumor microenvironment. The interlocked structure of iDNS provide a more rigid scaffold in comparison to double-stranded DNA for ligand assembly, which can help to control the spatial distribution of ligands with more accuracy. We have demonstrated that the pH-driven reversible reconfiguration of iDNS provides a powerful way to regulate the nanoscale distribution of T-cell receptors (CD3) on the cell surface. The relatively low pH value (pH 6.5) in a solid tumor was able to drive the springlike shrinking of iDNS and induce significant T-cell proliferation, leading to an enhanced antitumor effect, thus providing a tool for specifically inducing an immune response in a tumor for immunotherapy.

Nanoarchitectonics horizons: materials for life sciences

“…After binding, the aminated fullerene complex initiates the transfer of cytoplasmic myosin heavy chain 9 to the cell edge, thereby inhibiting cancer cell migration and the epithelial-to-mesenchymal transition process. 107 Kosuke Minami and co-workers have developed water-soluble cationic fullerenes, tetra-( piperazino) [60]fullerene epoxide-serum protein ternary complexes, for the effective delivery of highly unstable siRNA. The amphiphilic nature of the fullerene complex and its conjugation with protein forms a stable micelle that protects siRNA for safer delivery at the target site.…”

“…They found that the developed system is more stable than that of double-stranded DNA, which regulates the nanoscale distribution of the cluster of differentiation (CD3) receptor on the cell surface at low pH (tumor microenvironment). 60 In another study, pheophorbide A photosensitizers were grafted on a DNA backbone using phosphorothioate modification and small inhibitory RNAs (siRNA) along with a programmed death ligand were pooled together to form a supramolecular structure via self-assembly. The developed tetrahedron network was able to kill cells through photodynamic activity and simultaneously silence programmed death ligand expression for enhanced antitumor activity.…”

Stimuli-responsive nucleic acid nanostructures for efficient drug delivery

“…3c). 62 By encoding a cytosine-rich i-motif structure in interlocked circular DNA nanostructures, a spring-like shrinking was achieved in response to the relatively low pH value in tumors to regulate the nanoscale distribution of T-cell receptors (CD3) on the cell surface. This platform elicited significant T-cell proliferation and subsequently enhanced the antitumor effect.…”

Inflammatory pathophysiological mechanisms implicated in postpartum depression

“…T cell-based immunotherapy has received great attention in tumor treatments ( Zhang, K. et al, 2022 ) in recent years. Engineering T cells is a rapidly advancing technology and is a good strategy for stimulating T cells proliferation to effectively target tumors ( Belk et al, 2022 ).…”