DataVXAdvanced Functional MaterialsPaper
journal article·2025-08Open access

A DNA Nanomachine Reverses Mitochondrial Dysfunction by Cascaded Drug Release to Treat Osteoarthritis

Song Xue, Yang Zhao, Shiqian Huang, Guangfeng Ruan, Jianmao Chen, Hong Huang, Cuixi Wu, Jiang Li, Wei Hu, Yinan Zhang, Chao Zhang, Changhai Ding

Advanced Functional Materials· Volume 35· Issue 33
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Source abstract

Abstract

Abstract Mitochondrial dysfunction in chondrocytes is closely associated with osteoarthritis (OA) progression. However, the underlying mechanism remains elusive, and targeted OA therapies are lacking. Here, it is demonstrated that mitochondrial calcium (mito‐Ca 2+ ) content and energy metabolism are dysregulated in OA. Accordingly, a DNA nanomachine (DNM) is developed for OA treatment by reversing the mitochondrial dysfunction. The DNM used a programmable tetrahedral framework and incorporated dual targeting, switching, and therapeutic motifs. The targeting motifs contained a collagen II‐targeting peptide and an adenosine triphophate (ATP) aptamer to enable precise delivery into cartilage and mitochondria, respectively. Overexpressed matrix metalloproteinases (MMPs) in OA microenvironment triggered the MMP‐cleavable peptide switch and induced the release of mitochondrial open reading frame of the 12S rRNA‐c to promote ATP production. This result further triggered the release of DS16570511 conjugated to a sequence partially hybridized with ATP aptamer, inhibiting mito‐Ca 2+ uniporter and mitigating mito‐Ca 2+ overload under chronic inflammation. By leveraging sequential roles in delivery targeting, switch triggering, and therapeutic release, the DNM synergistically promoted cellular energy metabolism, inhibited mito‐Ca 2+ overload, and maintained extracellular matrix homeostasis. Consequently, cartilage degradation is significantly delayed in an OA model after treatment. This approach paves avenues for developing novel strategies to combat OA progression.
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Research context

Nanomaterials

OpenAlex topics: Advanced biosensing and bioanalysis techniques · ATP Synthase and ATPases Research · RNA Interference and Gene Delivery

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Clinical Research Centre Zhujiang Hospital Southern Medical University Guangzhou 510280 China

Department of Sports Medicine Peking University Shenzhen Hospital Shenzhen Peking University‐The Hong Kong University of Science and Technology Medical Center Shenzhen 518036 China

Clinical Research Centre Guangzhou First People's Hospital School of Medicine South China University of Technology Guangzhou 510180 China

Institute of Materiobiology Department of Chemistry College of Science Shanghai University Shanghai 200444 China

Department of Clinical Pharmacology The Second Affiliated Hospital of Anhui Medical University Hefei 230601 China

School of Chemical Science and Engineering Tongji University Shanghai 200092 China

Department of Neurosurgery Zhujiang Hospital Southern Medical University Guangzhou Guangdong 510280 China

National Center for Translational Medicine (Shanghai) SHU Branch Shanghai University Shanghai 200444 China

Guangdong Provincial Key Laboratory of Bone and Joint Degenerative Diseases Guangzhou Guangdong 510280 China

Menzies Institute for Medical Research University of Tasmania Hobart 7000 Australia

Funding

National Natural Science Foundation of China · Shenzhen Science and Technology Innovation Program · Basic and Applied Basic Research Foundation of Guangdong Province

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