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

• Published in: Advanced healthcare materials 2024-11, p.e2403212
• Main Authors: Wu, Yuansheng, Zhu, Yingjie, Chen, Jie, Song, Lili, Wang, Chunping, Wu, Yanglin, Chen, Yanyang, Zheng, Jiancheng, Zhai, Yuankun, Zhou, Xiang, Liu, Youwen, Du, Yawei, Cui, Wenguo
• Format: Article
• Language: English
• ISSN: 2192-2640; 2192-2659; 2192-2659
• DOI: 10.1002/adhm.202403212

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.