Targeting Osteoblast‐Osteoclast Cross‐Talk Bone Homeostasis Repair Microcarriers Promotes Intervertebral Fusion in Osteoporotic Rats

Abstract Balancing osteoblast‐osteoclast (OB‐OC) cross‐talk is crucial for restoring bone tissue structure and function. Current clinical drugs targeting either osteogenesis or osteoclastogenesis fail to effectively regulate cross‐talk, impeding efficient bone repair in osteoporosis patients. Ubiquitin‐specific protease 26 (USP26) is shown to coordinate OB‐OC cross‐talk by independently regulating β‐catenin and Iκb‐α. However, effective drugs for activating USP26 are still lacking. Here, they constructed bone homeostasis repair microcarriers (BHRC) that encapsulate Usp26 mRNA‐loaded lipid nanoparticles (mRNA@LNP) within MMPs‐responsive GelMA hydrogel microspheres. These microcarriers target the osteoporotic microenvironment and regulate OB‐OC cross‐talk, thereby facilitating intervertebral fusion in osteoporotic rats. Results demonstrate that mRNA@LNP exhibits uniform particle size and high transfection efficiency, while GelMA hydrogel microspheres possess excellent biocompatibility and MMP responsiveness, providing favorable cell survival space and controllable release of mRNA@LNP. The released LNP upregulates USP26 protein expression, effectively promoting osteogenesis while suppressing osteoclast formation. In vivo experiments show that injecting BHRC into the defect site of intervertebral discs in osteoporotic rats significantly promotes tail vertebrae fusion by responding to the microenvironment and regulating cell‐to‐cell cross‐talk. Thus, the BHRC holds great potential in regulating osteoporotic homeostasis, particularly in challenging bone defects such as intervertebral fusion in osteoporotic environments.