CD74-ENO2 axis drives glycolytic synovial macrophages in OA; targeted siRNA nanoparticles slow disease in mice
- Single-cell and spatial transcriptomics of mouse and human osteoarthritic synovium revealed an expanding, glycolysis-reliant, proinflammatory CD74+ macrophage population at the synovium-cartilage border.
- CD74 binds the glycolytic enzyme ENO2, promoting nuclear entry of HIF-1α/β-catenin and a self-reinforcing metabolic-inflammatory program.
- Myeloid CD74 deletion or drug blockade eased synovitis and cartilage damage in mouse OA models; intra-articular lipid nanoparticles carrying CD74 siRNA, guided by MIF-mimetic peptides, reached these macrophages and slowed disease.
💡 Points Based on the abstract
I would not bank on the mouse genetics alone: myeloid CD74 deletion is a clean target-validation experiment, but OA mice are mostly surgical models that skew toward inflammation more than human disease does. The harder question is delivery. A MIF-mimetic ligand on an LNP may hit CD74+ macrophages, but I want synovial clearance, off-target uptake in other CD74+ antigen-presenting cells, and knockdown duration in a human-sized joint.