Aptamer-Driven DNA Framework Switches for Clearing Programmed Cell Death-Ligand 1 Positive Extracellular Vesicles via...

The immune system employs molecular switches to maintain dynamic homeostasis, yet malignant cells often learn from these natural switches and ultimately evade immune surveillance, leading to immune tolerance and tumor deterioration. Chemically synthetic switches designed to redirect immune signaling pathways are highly desired for reversing this pathological trajectory but are rarely reported. Herein, we develop a synthetic DNA framework (DF) switch that reprograms macrophage-mediated immune clearance of Programmed Cell Death-Ligand 1 Positive (PD-L1⁺) extracellular vesicles (EVs) in vivo. This synthetic switch is composed of a ligand (Man₆)-terminated PD-L1-targeting aptamer (MJ5C) and a DF, termed hereinafter as MJ5C-Man₆-DF, which operates through a recognition-then-recruitment mechanism. Thus, in the "off state", MJ5C stably resides within the DF, retaining Man₆ in its inner cavity. However, upon target recognition, MJ5C switches to the "on state" and binds to PD-L1⁺ EVs, conferring conformational changes that allow coating of its terminal Man₆ on EVs. Man₆-coated EVs then recruit macrophages via the membrane receptor CD206, enabling efficient phagocytosis. MJ5C-Man₆-DFs were shown to perform with exceptional stability and specificity, augmenting αPD-L1 therapy by 90.7% while boosting T cell activation by 55% in vivo. Therefore, our aptamer-driven DF switch provides a strategy for precise immune reprogramming in the field of DNA-based molecular engineering.