A Modular Endogenous-Responsive DNA Nanosponge for Cancer-Selective RNA Demethylase Imaging and Concurrent...

Area of Science:

• Biochemistry
• Nanotechnology
• Cancer Research

Background:

• RNA demethylase, particularly FTO, is vital for m6A modification, making it a therapeutic target.
• Current methods for real-time FTO activity monitoring in cells face challenges with probe stability and tumor selectivity.
• Developing selective and stable probes is crucial for advancing FTO-targeted cancer diagnostics and therapeutics.

Purpose of the Study:

• To create a cancer-targeting, endogenously activated DNA nanosponge (DNS) platform for selective FTO imaging.
• To integrate FTO activity monitoring with photodynamic therapy for combined cancer treatment.
• To overcome limitations of existing probes by enhancing stability and tumor selectivity.

Main Methods:

• Constructed a DNA nanosponge (DNS) using rolling circle amplification, loaded with FTO-responsive DNAzyme probes (FDz) and zinc phthalocyanine (ZnPc).
• Utilized a glutathione (GSH)-cleavable disulfide linkage for FDz conjugation, enabling intracellular release upon cancer cell uptake.
• Demonstrated folate receptor-mediated internalization, GSH-triggered FDz release, FTO-mediated DNAzyme reactivation for fluorescence imaging, and ZnPc-induced photodynamic therapy.

Main Results:

• The FDz-ZnPc@DNS nanoplatform showed cancer-selective uptake and activation.
• Intracellular GSH successfully triggered the release of FDz, leading to FTO-mediated DNAzyme reactivation and amplified fluorescence.
• The system enabled precise FTO imaging and effective cancer cell destruction via photodynamic therapy both in vitro and in vivo.

Conclusions:

• The developed nanoplatform offers a robust and versatile approach for precise cancer imaging and therapy.
• This modular system merges targeted delivery and endogenous activation, demonstrating potential for adaptation to various sensing and therapeutic payloads.
• The study validates the feasibility of this integrated nanoplatform for advancing cancer diagnostics and treatment strategies.