MMP13-targeted siRNA-loaded micelles for diagnosis and treatment of posttraumatic osteoarthritis

Dongyang Zhou; Yan Wei; Shihao Sheng; Miaomiao Wang; Jiajing Lv; Bowen Zhao; Xiao Chen; Ke Xu; Long Bai; Yan Wu; Peiran Song; Liehu Cao; Fengjin Zhou; Hao Zhang; Zhongmin Shi; Jiacan Su

doi:10.1016/j.bioactmat.2024.04.010

MMP13-targeted siRNA-loaded micelles for diagnosis and treatment of posttraumatic osteoarthritis

Bioact Mater. 2024 Apr 23:37:378-392. doi: 10.1016/j.bioactmat.2024.04.010. eCollection 2024 Jul.

Authors

Dongyang Zhou^{1

2

3

4}, Yan Wei^{1

2}, Shihao Sheng⁵, Miaomiao Wang^{1

2

6}, Jiajing Lv^{1

2

3}, Bowen Zhao^{1

2

3}, Xiao Chen⁵, Ke Xu^{1

2}, Long Bai^{1

2}, Yan Wu^{1

2}, Peiran Song^{1

2}, Liehu Cao⁷, Fengjin Zhou⁸, Hao Zhang⁵, Zhongmin Shi⁹, Jiacan Su^{1

2

5}

Affiliations

¹ Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China.
² National Center for Translational Medicine (Shanghai), Shanghai University, Shanghai, 200444, China.
³ College of Medicine, Shanghai University, Shanghai, 200444, China.
⁴ School of Environmental and Chemical Engineering, Shanghai University, Shanghai, 200444, China.
⁵ Department of Orthopedic, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
⁶ Department of Rehabilitation Medicine, Shanghai Zhongye Hospital, Shanghai, 200941, China.
⁷ Department of Orthopedics, Shanghai Baoshan Luodian Hospital, Baoshan District, Shanghai, 201908, China.
⁸ Department of Orthopaedics, Honghui Hospital, Xi'an Jiao Tong University, Xi'an, 710000, China.
⁹ Department of Orthopedics, Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, 200233, China.

Abstract

Posttraumatic osteoarthritis (PTOA) patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions are less effective. Early PTOA is characterized by overexpressed matrix metalloprotease 13 (MMP13). Herein, we constructed an integrated diagnosis and treatment micelle modified with MMP13 enzyme-detachable, cyanine 5 (Cy5)-containing PEG, black hole quencher-3 (BHQ3), and cRGD ligands and loaded with siRNA silencing MMP13 (siM13), namely ERMs@siM13. ERMs@siM13 could be cleaved by MMP13 in the diseased cartilage tissues to detach the PEG shell, causing cRGD exposure. Accordingly, the ligand exposure promoted micelle uptake by the diseased chondrocytes by binding to cell surface αvβ3 integrin, increasing intracellular siM13 delivery for on-demand MMP13 downregulation. Meanwhile, the Cy5 fluorescence was restored by detaching from the BHQ3-containing micelle, precisely reflecting the diseased cartilage state. In particular, the intensity of Cy5 fluorescence generated by ERMs@siM13 that hinged on the MMP13 levels could reflect the PTOA severity, enabling the physicians to adjust the therapeutic regimen. Finally, in the murine PTOA model, ERMs@siM13 could diagnose the early-stage PTOA, perform timely interventions, and monitor the OA progression level during treatment through a real-time detection of MMP13. Therefore, ERMs@siM13 represents an appealing approach for early-stage PTOA theranostics.

Keywords: Early-stage posttraumatic osteoarthritis (PTOA); Fluorescence imaging; Matrix metalloprotease 13 (MMP 13); Micelles; siRNA delivery.