In vivo circRNA-engineered macrophages mediate localized MMP9 neutralization to rejuvenate aged bone

Area of Science:

• Biomedical Engineering
• Immunotherapy
• Aging Research

Background:

• Aging leads to skeletal issues like osteoporosis and osteoarthritis, with unclear mechanisms and limited therapies.
• Transcriptomics reveal elevated Matrix Metalloproteinase 9 (MMP9) in aging bone and serum, suggesting its role in skeletal aging.
• Systemic MMP9 neutralization presents a potential immunotherapy strategy for age-related skeletal disorders.

Purpose of the Study:

• To develop an in vivo immunotherapy targeting MMP9 for skeletal aging.
• To engineer macrophages as cellular factories for anti-MMP9 antibodies using a circRNA-based strategy.
• To evaluate the efficacy of a novel apoptosis-mimicking lipid nanoparticle (aMMP9-LNP) for targeted MMP9 neutralization in aged mice.

Main Methods:

• Developed a circRNA-based antibody-engineering strategy to convert macrophages into anti-MMP9 antibody producers.
• Created an optimized apoptosis-mimicking lipid nanoparticle (aMMP9-LNP) incorporating phosphatidylserine for enhanced macrophage uptake.
• Administered aMMP9-LNP systemically in aged mice to leverage inflammation-guided chemotaxis for targeted MMP9 neutralization.
• Assessed effects on stem cell senescence, osteogenesis, fracture repair, cartilage degeneration, and molecular markers (p21, MMP3).

Main Results:

• Systemic aMMP9-LNP treatment in aged mice reduced stem cell senescence, enhanced osteogenesis, and accelerated fracture repair.
• The therapy mitigated cartilage degeneration, indicating a protective effect against osteoarthritis.
• Mechanistically, MMP9 blockade normalized osteoblast-osteoclast balance, reduced senescence-associated secretory phenotype, and lowered p21/MMP3 levels.
• Biodistribution studies confirmed bone-targeted delivery and preserved tissue homeostasis.

Conclusions:

• MMP9 is identified as a key effector molecule in skeletal aging.
• The developed in vivo mRNA immunotherapy using aMMP9-LNP is effective in treating age-related skeletal deterioration in mice.
• This approach demonstrates translational potential for managing osteoporosis, delayed fracture healing, and osteoarthritis in aging populations.