Mitochondria Rewiring by Polyphenol‐Copper Nanodots to Truncate Mitochondrial‐Endoplasmic Reticulum Crosstalk for Acute Kidney Injury Therapy

作者：Jiaojiao Zhang, Jingyi Li, Xue Jiang, Qirui Wang, Kaidi Zhang, Hao Huang, Zifan Cheng, Zhu Yang, Weijun Tong, Lie Ma, Jianghua Chen, Zhengwei Mao, Hong Jiang · 发表于：Advanced Materials · 年份：2025 · DOI：10.1002/adma.202508379 · 被引用次数：5 · 研究领域：Advanced Nanomaterials in Catalysis、Mitochondrial Function and Pathology、Dialysis and Renal Disease Management

Aberrant mitochondria-endoplasmic reticulum (ER) interactions at mitochondria-associated membranes (MAMs) drive renal tubular cell injury in acute kidney injury (AKI), exacerbating oxidative stress, calcium dysregulation, and homeostasis disruption. However, targeted intervention remains challenging. To address this challenge, this study employs gallic acid-modified polyphenol-copper nanodots (GA-Cu) to target tubular mitochondria and ameliorate AKI by rewiring organelle communication. Following systemic administration, the ultrasmall GA-Cu nanodots readily traverse the renal filtration barrier and are internalized by tubular cells. Their surface polyphenol composition enables precise enrichment around mitochondria, where they not only scavenge reactive oxygen species but also disrupt the core MAM tethering complex-the IP3R-GRP75-VDAC1 axis. In vitro and in vivo studies demonstrate that GA-Cu remodels mitochondria-ER interfaces, significantly suppressing pathological MAM formation. This intervention attenuates ER-to-mitochondria calcium transfer and restores mitochondrial function, resulting in remarkable renal protection. Hence, this refined cellular regulation is expected to offer substantial prospects for activating new subcellular compartment-specific homeostatic effects.