# mRNA-Based Combination Therapy for Inflammation-Driven Osteoarthritis Induced by Monosodium Iodoacetate

## TL;DR

This study explores using mRNA therapy to treat osteoarthritis by targeting both inflammation and cartilage health in a rat model.

## Contribution

The novel contribution is the demonstration of synergistic effects from combining anti-inflammatory and cartilage-supporting mRNAs in treating osteoarthritis.

## Key findings

- IL-1Ra mRNA reduced joint inflammation, pain, and swelling in OA.
- RUNX1 mRNA supported cartilage structure but had limited effect under strong inflammation.
- Combining IL-1Ra and RUNX1 mRNAs provided enhanced chondroprotection and bone preservation.

## Abstract

Background/Objectives: Osteoarthritis (OA) is a progressive joint disease characterized by inflammation, cartilage degradation, and subchondral bone changes, for which effective disease-modifying therapies are lacking. Messenger RNA (mRNA)-based therapeutics offer a versatile approach to modulate joint pathology, but their application to OA remains limited. Methods: We evaluated intra-articular delivery of therapeutic mRNAs using polyplex nanomicelles, a non-inflammatory and minimally invasive carrier system, in a rat model of inflammation-driven OA induced by monosodium iodoacetate (MIA). Results: IL-1 receptor antagonist (IL-1Ra) mRNA reduced synovial inflammation and alleviated pain and swelling. RUNX1 mRNA, a transcription factor critical for chondrogenesis, supported chondrocyte viability, type II collagen expression, and cartilage structure. Under conditions of pronounced inflammation, however, the protective effects of RUNX1 mRNA alone were modest. Notably, combined administration of IL-1Ra and RUNX1 mRNAs produced synergistic therapeutic benefits, with enhanced chondroprotection and preservation of subchondral bone integrity. Conclusions: These findings suggest that while RUNX1 is essential for maintaining cartilage homeostasis, effective control of joint inflammation is required for its therapeutic activity. Dual mRNA therapy delivered by polyplex nanomicelles therefore represents a promising strategy to address the multifactorial pathology of OA.