Boosting mRNA‐Engineered Monocytes via Prodrug‐Like Microspheres for Bone Microenvironment Multi‐Phase Remodeling

Abstract Monocytes, as progenitors of macrophages and osteoclasts, play critical roles in various stages of bone repair, necessitating phase‐specific regulatory mechanisms. Here, icariin (ICA) prodrug‐like microspheres (ICA@GM) are developed, as lipid nanoparticle (LNP) transfection boosters, to construct mRNA‐engineered monocytes for remodeling the bone microenvironment across multiple stages, including the acute inflammatory and repair phases. Initially, ICA@GM is prepared from ICA‐conjugated gelatin methacryloyl via a microfluidics system. Then, monocyte‐targeting IL‐4 mRNA‐LNPs are then prepared and integrated into injectable microspheres (mRNA‐ICA@GM) via electrostatic and hydrogen bond interactions. After bone‐defect injection, LNPs are controlled released from mRNA‐ICA@GM within 3 days, rapidly transfecting monocytes for monocyte IL‐4 mRNA‐engineering, which effectively suppressed acute inflammatory responses via polarization programming and paracrine signaling. Afterwards, ICA is sustainably released as well via cleavable boronate esters across multiple stages, cooperatively boosting the mRNA‐engineered monocytes to inhibit coenocytic fusion and osteoclastic function. Both in vitro and in vivo data indicated that mRNA‐ICA@GM can not only reverse the inflammatory environment but also suppress monocyte‐derived osteoclast formation to accelerate bone repair. In summary, mRNA‐engineered monocytes and ICA prodrug‐like microspheres are combined to achieve long‐lasting multi‐stage bone microenvironment regulation, offering a promising repair strategy.