Injectable CRISPRa-microspheres for targeted A20 activation rescue age-related osteogenic impairment via senescence mitigation.

Jie Chen, Zhen Wang, Yawei Du, Baikun Liu, Yanyang Chen, Gang Chen, Wenguo Cui

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, 197 Ruijin 2nd Road, Shanghai, 200025, PR China. · pubmed

Paper

Abstract

Age-related osteogenic failure in bone defect repair remains a significant clinical challenge, primarily due to persistent chronic inflammation-induced stem cell senescence. To address this, we engineered injectable CRISPRa-based gene-editing microspheres (GEMs), utilizing microfluidic-synthesized lipid nanoparticles (cLNPs) to co-deliver dCas9-VP64/sgRNA. This platform allows for precise spatiotemporal activation of tumor necrosis factor alpha-induced protein 3 (TNFAIP3/A20) within bone marrow stromal cells (BMSCs), effectively reprogramming the senescence-osteogenesis axis. Our study identifies A20 as a key regulator of the senescence-associated secretory phenotype (SASP) and osteogenic impairment in aged BMSCs. In vitro, GEMs reduced senescence markers (p16 and p21) by over 30 %, while increasing osteogenic gene expression (RUNX2 and ALP) by 4 ∼ 5-fold, and suppressed inflammatory cytokines IL-6 and TNF-α by more than 30 %. In vivo, in aged mice with critical-sized bone defects, GEMs achieved a significant bone regeneration and promoted vascularization 3.1 times faster (CD31

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The paper claims that injectable CRISPRa-microspheres can mitigate age-related osteogenic impairment by activating A20 in bone marrow stromal cells. This research addresses a root cause of aging-related decline in bone regeneration, focusing on cellular senescence and inflammation, which are key factors in the aging process.

Author of this paper? Send a correction.