Bioinspired miRNA-Responsive Ca <sup>2+</sup> Nanoregulator with Dual Interference Pathways and Self-Amplifying Cascade for Tumor-Targeted Mitochondrial Dysfunction
Jinkun Huang, Qin Xiang, Lei Shuai, Shuangshuang Yang, Jing Xu, Yaru Cheng, Youming Feng, Yufan Zhang, Zijia Zhou, Jiale Cheng, Youcong Gong, Jinze Li, Haifeng Dong
Abstract
Disrupting mitochondrial calcium ion (Ca 2+ ) homeostasis in tumor cells has emerged as a potent anticancer strategy, however, achieving precise, spatiotemporal control of mitochondrial Ca 2+ overload poses a significant challenge. Herein, we present a bioinspired miRNA-responsive Ca 2+ nanoregulator (Cu 2 O@Dz) that orchestrates endogenous ion flux through a multistage cascade to induce tumor-specific mitochondrial dysfunction. In this design, hairpin-structured DNAzymes (Dz) are conjugated to cuprous oxide (Cu 2 O) nanoparticles: within the acidic and H 2 O 2 -rich tumor microenvironment, the Cu 2 O core catalyzes site-specific Fenton-like reactions to generate hydroxyl radicals (•OH), which activate TRPA1 channels on the cell membrane and thereby trigger a robust influx of extracellular Ca 2+ . Concurrently, the Dz component functions as a dual-mode biosensor–actuator: recognition of overexpressed miRNA-21 produces a fluorescent signal for real-time diagnosis monitoring, while cleavage of miRNA-25 alleviates suppression of the mitochondrial calcium uniporter (MCU), thereby promoting mitochondrial Ca 2+ uptake. The synergistic coupling of a TRPA1-mediated cytosolic Ca 2+ surge with MCU-driven mitochondrial import establishes a unidirectional Ca 2+ gradient, culminating in irreversible mitochondrial Ca 2+ overload and potent tumor cell apoptosis. This work not only demonstrates an efficiently spatiotemporal coordination of dual ion-interference pathways for precision targeting but also establishes a versatile framework for organelle specific modulation of pathological ion fluxes in precision oncology.