Delivery of GAS5 by LNP promotes tendon-bone healing in rotator cuff injury

It is observed in clinical practice that worse healing in rotator cuff tear (RCT) is closely associated with osteoporosis in patients. Herein, from the statistical analysis, we further confirmed that the RCT is significantly increased in postmenopausal women who suffer from decreased bone mineral density (BMD), suggesting intervention of osteoporosis as a potential strategy in the management of RCT in aged women. Our previous studies showed that Growth arrest-specific 5 (GAS5), a long non-coding RNA (lncRNA), could promote bone formation, and alleviate osteoporosis. Herein, we demonstrated an enhancement of RCT healing by intraarticular administration of the GAS5 delivered with lipid nanoparticles (LNPs). Firstly, different kinds of ionizable lipids were applied to screen the capability of LNPs to deliver GAS5 <i>in vitro</i> to bone marrow mesenchymal stem cells (BMSCs) and the best-performing lipid was applied for <i>in vivo</i> evaluation in treating RCT rat models with osteoporosis by intraarticular injection. We found that GAS5-LNPs could improve bone quality and macrophage transformation into M2 type of the models with osteoporosis and facilitate healing of RCT. The therapeutic outcome with RCT rats demonstrated that tendon morphology, mechanical properties and bone quality of the rotator cuff were greatly improved. Thus, this study provides a new strategy to treat RCT by improving bone quality with formulated GAS5 by LNP, which is promising for clinical application.