Bioinspired miRNA-Responsive Ca²⁺ Nanoregulator with Dual Interference Pathways and Self-Amplifying Cascade for...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Mitochondrial calcium ion (Ca²⁺) homeostasis disruption is a key anticancer strategy.
• Precise spatiotemporal control of mitochondrial Ca²⁺ overload remains a challenge in cancer therapy.

Purpose of the Study:

• To develop a miRNA-responsive nanoregulator for tumor-specific mitochondrial dysfunction.
• To achieve precise, spatiotemporal control of mitochondrial Ca²⁺ overload for cancer treatment.

Main Methods:

• Conjugation of DNAzymes (Dz) to cuprous oxide (Cu₂O) nanoparticles to create Cu₂O@Dz.
• Utilizing the tumor microenvironment's acidity and H₂O₂ to generate hydroxyl radicals (•OH) via Fenton-like reactions.
• Employing Dz as a dual-mode biosensor-actuator for miRNA-21 detection and miRNA-25 cleavage to modulate mitochondrial calcium uniporter (MCU).

Main Results:

• Cu₂O@Dz induced tumor-specific mitochondrial dysfunction by orchestrating endogenous ion flux.
• TRPA1 channel activation led to extracellular Ca²⁺ influx, while miRNA-25 cleavage promoted mitochondrial Ca²⁺ uptake.
• Synergistic Ca²⁺ overload resulted in potent tumor cell apoptosis.

Conclusions:

• The Cu₂O@Dz nanoregulator enables efficient spatiotemporal coordination of dual ion-interference pathways for precision targeting.
• This platform provides a versatile framework for organelle-specific modulation of pathological ion fluxes in precision oncology.
• The study demonstrates a potent anticancer strategy by inducing irreversible mitochondrial Ca²⁺ overload.