AUTHOR=Zhang Yuan , Li Xu , Li Hao , Zhang Ruiyang , Zhang Ti , Juma Talante , Zhou Yongfei , Guo Quanyi , Zhao Hui , Cao Yongping 

TITLE=Anti-inflammatory therapy for tendinopathy using Il1rn mRNA encapsulated in SM102 lipid nanoparticles

JOURNAL=Frontiers in Bioengineering and Biotechnology

VOLUME=Volume 13 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2025.1641236

DOI=10.3389/fbioe.2025.1641236

ISSN=2296-4185

ABSTRACT=Tendinopathy treatment is hindered by persistent inflammation and irreversible matrix degradation, with current therapies offering transient symptom relief without addressing disease progression. Here, we developed an mRNA-based anti-inflammatory strategy utilizing SM102 lipid nanoparticles (LNPs) to deliver interleukin-1 receptor antagonist (Il1rn) mRNA for tendon repair. SM102-LNPs demonstrated efficient transfection of primary tendon stem cells, sustaining IL-1RA protein expression for over 72 h and neutralizing IL-1β-induced inflammatory cascades. In vitro, IL-1RA suppressed pro-inflammatory cytokines (TNF-α, IL-6, iNOS), restored collagen I/III balance, and enhanced cell migration. In collagenase-induced tendinopathy mice, a single SM102-Il1rn mRNA injection attenuated inflammation, reduced MMP1/13 expression, and improved collagen alignment within 1 week. By 4 weeks, treated tendons exhibited functional recovery with normalized gait patterns. Transcriptomics revealed dual modulation of IL-1 signaling and extracellular matrix (ECM) remodeling pathways, alongside macrophage polarization and oxidative stress regulation. Systemic safety was confirmed by unaltered serum biomarkers and organ histology. This SM102-Il1rn mRNA therapy enables spatiotemporally controlled anti-inflammatory therapy, providing a promising non-surgical solution for refractory tendinopathies. Its adaptable design allows expansion to other regenerative targets, advancing precision treatment for musculoskeletal degeneration.