Functionalized DNA Nanomaterials Targeting Toll‐Like Receptor 4 Prevent Bisphosphonate‐Related Osteonecrosis of the Jaw via Regulating Mitochondrial Homeostasis in Macrophages

Author:

Zhang Tao1,Ma Huangshui2,Zhang Xiaolin2,Shi Sirong2,Lin Yunfeng1ORCID

Affiliation:

1. State Key Laboratory of Oral Diseases National Clinical Research Center for Oral Diseases Med‐X Center for Materials West China Hospital of Stomatology Sichuan University Chengdu Sichuan 610041 P. R. China

2. State Key Laboratory of Oral Diseases West China Hospital of Stomatology Sichuan University Chengdu 610041 P. R. China

Abstract

AbstractImbalance of macrophage polarization characterized by an increase in the percentage of pro‐inflammatory M1 macrophages and a decrease in anti‐inflammatory M2 macrophages is considered a critical pathogenic mechanism of bisphosphonate‐related osteonecrosis of the jaws (BRONJ). Because high levels of Toll‐like receptor 4 (TLR4) mediates mitochondrial dyshomeostasis in Zoledronic Acid (ZA)‐treated M1 macrophages, tetrahedral DNA nanomaterial (TDN)‐modified with TLR4‐siRNA on each vertex (TDN‐TLR4‐4siR) with excellent biocompatibility is synthesized. This novel TDN‐TLR4‐4siR nanomaterial reverses the polarization phenotype imbalance decreasing the percentage of M1 RAW264.7 macrophages. Mitochondrial dynamics analysis shows a shift from short rod‐like ultrastructure to elongated shapes with more mitochondrial network continuity in ZA‐primed M1 macrophages after treatment with TDN‐TLR4‐4siR, along with elevated expression of Mfn1 and Mfn2. TDN‐TLR4‐4siR further reduces intracellular ROS production and restored mitochondrial membrane potential. Furthermore, decreased sequestra formation and accelerated healing of the extraction wound are observed in the TDN‐TLR4‐4siR group, resulting in decreased incidence of rat BRONJ via reprogramming polarized macrophages. Consequently, this study establishes a novel strategy using TDN‐TLR4‐4siR nanomaterial to regulate mitochondrial homeostasis of polarized macrophages to prevent BRONJ.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Electrochemistry,Condensed Matter Physics,Biomaterials,Electronic, Optical and Magnetic Materials

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