# Nano MiRNA‐Functionating Tetrahedral Framework Nucleic Acid for Cartilage‐Targeted Ferritinophagy Modulation to Attenuate Temporomandibular Joint Osteoarthritis

## TL;DR

A new nanodelivery system using miR-143-3p helps treat temporomandibular joint osteoarthritis by reducing harmful cell death.

## Contribution

A novel tFNA-based miRNA delivery system is developed for targeted TMJOA therapy.

## Key findings

- tFNAs-143 shows excellent cellular uptake in chondrocytes.
- tFNAs-143 mitigates TMJOA progression by inhibiting ferritinophagy-mediated ferroptosis.
- The system improves miRNA delivery efficiency and stability.

## Abstract

Current clinical interventions lack effective strategies to arrest temporomandibular joint osteoarthritis (TMJOA) progression. Emerging evidence highlights the therapeutic potential of microRNAs (miRNAs) in osteoarthritis (OA) management, though critical challenges persist regarding delivery efficiency, including unsatisfactory cellular uptake, immunogenicity, and structural instability of miRNA‐based therapeutics. Considering the powerful editability of tetrahedral framework nucleic acids (tFNAs) for gene delivery, a novel nanoscale gene delivery system using tetrahedral framework nucleic acids functionalized with miR‐143‐3p (tFNAs‐143) is engineered. Through comprehensive in vivo modeling of TMJOA destabilization and in vitro simulation of IL‐1β‐induced inflammatory microenvironments, the therapeutic efficacy and molecular mechanisms underlying OA pathophysiology of tFNAs‐143 are systematically investigated. The results demonstrate that tFNAs‐143 exhibits excellent cellular internalization in chondrocytes and effectively mitigates TMJOA progression by impeding ferritinophagy‐mediated ferroptosis. This study advances miRNA delivery technology for TMJOA therapy, deepens the insights into TMJOA pathogenesis, and proposes a promising nanotherapeutic strategy for developing targeted TMJOA therapies.

Current temporomandibular joint osteoarthritis (TMJOA) treatments lack progression control. MicroRNAs (miRNAs) offer therapeutic potential but face delivery hurdles. A novel nanodelivery system is developed using tetrahedral framework nucleic acids functionalized with miR‐143‐3p (tFNAs‐143). Tested in TMJOA models and inflammatory conditions, tFNAs‐143 mitigate TMJOA progression by inhibiting ferritinophagy‐mediated ferroptosis. This advances both TMJOA treatment and pathological understanding.© 2026 WILEY‐VCH GmbH