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Aptamer-Driven DNA Framework Switches for Clearing Programmed Cell Death-Ligand 1 Positive Extracellular Vesicles via
Liyan Zheng1, Jingchen Zhang2, Panmin Lei3
1Zhejiang Cancer Hospital, The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
Abstract:
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.
Insights
Researchers developed a synthetic DNA framework (DF) switch to reprogram macrophages for clearing Programmed Cell Death-Ligand 1 positive (PD-L1+) extracellular vesicles. This engineered switch enhances anti-cancer immunity and immunotherapy efficacy.
Area of Science:
- Biotechnology
- Molecular Engineering
- Immunology
Background:
- The immune system uses molecular switches for homeostasis, but cancer cells exploit these to evade immune surveillance, causing immune tolerance.
- Synthetic molecular switches are needed to redirect immune signaling and reverse tumor progression, but are rarely reported.
Purpose of the Study:
- To develop a synthetic DNA framework (DF) switch for reprogramming macrophage-mediated immune clearance of Programmed Cell Death-Ligand 1 positive (PD-L1+) extracellular vesicles (EVs) in vivo.
- To engineer a novel aptamer-driven DF switch for precise immune reprogramming.
Main Methods:
- A synthetic DNA framework (DF) switch, MJ5C-Man6-DF, was designed using a PD-L1-targeting aptamer (MJ5C) and a DF.
- The switch operates via recognition-then-recruitment: MJ5C binds PD-L1+ EVs, exposing Man6 to recruit macrophages through CD206 for phagocytosis.
Main Results:
- The MJ5C-Man6-DF switch demonstrated exceptional stability and specificity in vivo.
- The switch augmented alphaPD-L1 therapy by 90.7% and boosted T cell activation by 55%.
Conclusions:
- The aptamer-driven DF switch provides a novel strategy for precise immune reprogramming.
- This DNA-based molecular engineering approach shows promise for enhancing cancer immunotherapy.
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