Tetrahedral Framework Nucleic Acid-Based Cepharanthine Attenuates TMJOA via cGAS-STING-NF-κB Pathway Modulation and Macrophage Reprogramming

Shibo Liu, State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.
Hanghang Liu, State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.
Qiheng Yang, State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.
Xuehan Tang, State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.
Linyi Liu, Maine Medical Center Research Institute, Maine Medical Center, Scarborough, Maine 04074, United States.
Yao Liu, State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.
Wangyang Ying, Sichuan University, No.24 South Section 1, Yihuan Road, Chengdu 610065, China.
Yunfeng Lin, State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.

Document Type

Article

Publication Date

1-6-2026

Journal Title

ACS applied materials & interfaces

Abstract

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative joint disease characterized by cartilage degradation, subchondral bone remodeling, and chronic inflammation for which effective therapies remain lacking. In this study, we develop a cepharanthine-loaded tetrahedral framework nucleic acid nanoplatform (tFNA@Cep) and evaluate its physicochemical properties, biological performance, and therapeutic potential in TMJOA. The nanostructure exhibits excellent stability, favorable size distribution, and efficient cellular uptake, with preserved structural integrity under physiological conditions. In a murine model of TMJOA induced by unilateral anterior crossbite, tFNA@Cep treatment significantly improved cartilage thickness and subchondral bone architecture, accompanied by restored expression of Col II and RUNX2. Mechanistically, tFNA@Cep promotes macrophage polarization toward an anti-inflammatory M2 phenotype and suppresses activation of the cGAS-STING-NFκB pathway and intracellular ROS production. Moreover, the conditioned medium from tFNA@Cep-treated macrophages enhances anabolic gene expression in chondrocytes, indicating an immunomodulatory effect on cartilage regeneration. Collectively, these findings demonstrate that tFNA@Cep functions as a multifunctional nanotherapeutic agent capable of integrating drug delivery, inflammation resolution, and osteochondral repair, providing a promising strategy for the treatment of TMJOA and related joint disorders.

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