ZIF-8-mediated co-delivery of L-arginine and functional nucleic acids for monitoring and evaluating nitric oxide antitumor effects.

The metal-organic framework (MOF) material ZIF-8 was used as a nanocarrier to construct a platform capable of simultaneously delivering L-arginine and functional nucleic acid molecules. This system enables real-time monitoring of the spatial displacement of apoptosis-related enzymes as well as monitoring of the early stages of apoptosis during NO-mediated tumor therapy. ZIF-8 exhibits excellent biocompatibility and acid sensitivity, allowing it to degrade in the tumor microenvironment and release its functional molecules. In this platform, L-arginine and functional nucleic acid molecules that specifically recognize the Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APE1) enzyme (including initiator strand IND, hairpin probes H1 and H2, and H2 labeled with Cy 5 and BHQ-2) were co-packaged into ZIF-8 in a single step for the first time, forming DNA/L-Arg@ZIF-8 nanoprobes. Inside cells, L-arginine is catalyzed by endogenous NO synthase to produce nitric oxide (NO), which induces APE1 to transport from the nucleus to the cytoplasm. APE1 specifically recognizes and cleaves the AP site in the molecular probe, releasing IND, triggering the catalytic hairpin assembly (CHA) reaction, and restoring FRET fluorescence signals, thus enabling the visualization of APE1's spatial displacement during apoptosis. In vivo results verified that DNA/L-Arg@ZIF-8 can effectively suppress tumor growth. More importantly, this nanosystem enables the prediction of therapeutic response in advance. This system not only achieves the synergistic delivery of NO donors and signal probes but also provides a dynamic monitoring method for the NO-induced apoptosis mechanism.