LNP-mRNA-engineered fibroblasts delivering TNF-α antibodies alleviate intervertebral disc degeneration by modulating the inflammatory microenvironment

The inflammatory environment mediated by TNF-α in the intervertebral disc can reduce the transfection efficiency of LNPs. • Engineered fibroblasts overexpressing TNF-α antibodies exhibit resistance to the decline in proliferation ability and activity induced by the inflammatory microenvironment. • Engineered fibroblasts rescue the inflammatory phenotype and ameliorate ECM homeostasis of degenerated nucleus pulposus cells in IVDD models in vitro and in vivo. Lumbar intervertebral disc degeneration (IVDD) is a prevalent degenerative condition lacking effective early-stage treatments. While fibroblast cell therapy and mRNA therapeutics represent promising approaches, their efficacy is limited by the inflammatory microenvironment of degenerated discs, which affects the delivery efficiency and compromises cell viability and gene delivery. To overcome these challenges, we developed an LNP-mRNA-engineered fibroblast strategy, utilizing fibroblasts as a “Trojan horse” for targeted mRNA delivery. In IVDD progression, inflammatory factors, particularly TNF-α, accumulate and exacerbate degeneration. Engineered fibroblasts mitigates TNF-α-induced senescence and proliferation arrest in inflammatory conditions, counteracts nucleus pulposus inflammation, and restores extracellular matrix production. In a rat IVDD model, engineered fibroblasts significantly improved disc height and showed superior therapeutic effects compared to naive fibroblasts. These results highlight the dual therapeutic mechanism of our approach, i.e. combining cell therapy with mRNA delivery, and its clinical potential in the treatment of IVDD. Download: Download high-res image (105KB) Download: Download full-size image