2. Academic Validation
  3. Targeted Macrophage CRISPR-Cas13 mRNA Editing in Immunotherapy for Tendon Injury

Targeted Macrophage CRISPR-Cas13 mRNA Editing in Immunotherapy for Tendon Injury

  • Adv Mater. 2024 Feb 1:e2311964. doi: 10.1002/adma.202311964.
Shuo Wang 1,  Yao Xiao 1,  Jian Tian 2,  Bo Dai 3,  Zaijin Tao 1,  Jingwen Liu 1,  Zhenyu Sun 1,  Xuanzhe Liu 1,  Yanhao Li 1,  Gang Zhao 2,  Yong Cui 4,  Fei Wang 5,  Shen Liu 1
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
  • 2 Department of Orthopedics, Soochow University Affiliated Wuxi Ninth People's Hospital, Wuxi, 214061, China.
  • 3 Department of Hematology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
  • 4 School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules and State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 5 Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
PMID: 38302097 DOI: 10.1002/adma.202311964
Abstract

CRISPR-Cas13 holds substantial promise for tissue repair through its RNA editing capabilities and swift catabolism. However, conventional delivery methods fall short in addressing the heightened inflammatory response orchestrated by macrophages during the acute stages of tendon injury. In this investigation, macrophage-targeting cationic Polymers are systematically screened to facilitate the entry of Cas13 ribonucleic-protein complex (Cas13 RNP) into macrophages. Notably, SPP1 (OPN encoding)-producing macrophages are recognized as a profibrotic subtype that emerges during the inflammatory stage. By employing ROS-responsive release mechanisms tailored for macrophage-targeted Cas13 RNP editing systems, the overactivation of SPP1 is curbed in the face of an acute immune microenvironment. Upon encapsulating this composite membrane around the tendon injury site, the macrophage-targeted Cas13 RNP effectively curtails the emergence of injury-induced SPP1-producing macrophages in the acute phase, leading to diminished fibroblast activation and mitigated peritendinous adhesion. Consequently, this study furnishes a swift RNA editing strategy for macrophages in the inflammatory phase triggered by ROS in tendon injury, along with a pioneering macrophage-targeted carrier proficient in delivering Cas13 into macrophages efficiently.

Keywords

Cas13 RNP; SPP1; macrophage targeting; peritendinous adhesion.

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