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

Area of Science:

• Biomaterials Science
• Regenerative Medicine
• Immunology

Background:

• Monocytes are crucial for bone repair, acting as progenitors for macrophages and osteoclasts.
• Effective bone repair requires phase-specific regulation of these cellular processes.
• Current strategies often lack multi-stage control over the bone microenvironment.

Purpose of the Study:

• To develop mRNA-engineered monocytes combined with icariin (ICA) prodrug-like microspheres (ICA@GM) for multi-stage bone repair.
• To investigate the ability of these engineered monocytes to modulate the bone microenvironment during acute inflammation and repair phases.
• To assess the therapeutic potential for accelerating bone healing by controlling inflammatory responses and osteoclastogenesis.

Main Methods:

• Preparation of ICA-conjugated gelatin methacryloyl microspheres (ICA@GM) using microfluidics.
• Development of monocyte-targeting IL-4 mRNA-lipid nanoparticles (LNPs) and integration into injectable microspheres (mRNA-ICA@GM).
• In vitro and in vivo evaluation of controlled release, monocyte transfection, inflammatory suppression, and bone repair acceleration.

Main Results:

• Controlled release of LNPs and mRNA-ICA@GM successfully engineered monocytes, suppressing acute inflammation via polarization and paracrine signaling.
• Sustained release of ICA from microspheres boosted engineered monocytes, inhibiting osteoclast formation and function.
• Both in vitro and in vivo studies demonstrated accelerated bone repair, reversal of inflammatory environment, and suppressed osteoclastogenesis.

Conclusions:

• mRNA-engineered monocytes combined with ICA prodrug-like microspheres offer a promising strategy for long-lasting, multi-stage regulation of the bone microenvironment.
• This approach effectively manages inflammation and osteoclast formation, leading to accelerated bone repair.
• The developed system provides a novel therapeutic avenue for bone defect regeneration.