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Engineered Exosomes with ATF5-Modified mRNA Loaded in Injectable Thermogels Alleviate Osteoarthritis by Targeting the
Tiancong Ma1,2, Guangyu Xu1,2, Tian Gao1,2
1Department of Orthopaedic Surgery, Huashan Hospital Fudan University, 12th Wulumuqi Middle Road, Jing'an District, Shanghai 200040, China.
ACS Applied Materials & Interfaces
|April 16, 2024
Summary
This study shows that engineered exosomes carrying modified mRNA for ATF5, encapsulated in a hydrogel, effectively treat osteoarthritis by improving chondrocyte function and preserving cartilage. This approach offers a promising therapeutic strategy for osteoarthritis progression.
Area of Science:
- Biomedical Engineering
- Regenerative Medicine
- Molecular Biology
Background:
- Osteoarthritis (OA) involves chondrocyte mitochondrial dysfunction and extracellular matrix (ECM) imbalances.
- The mitochondrial unfolded protein response (UPRmt) is crucial for chondrocyte homeostasis and mitochondrial quality control (MQC).
- Activating transcription factor 5 (ATF5) plays a key role in UPRmt activation, mitigating inflammation, and balancing chondrocyte metabolism.
Purpose of the Study:
- To investigate the therapeutic potential of ATF5 delivery for osteoarthritis.
- To develop a sustained-release system for engineered exosomes carrying Atf5-modified mRNA (modAtf5).
- To evaluate the efficacy of hydrogel-encapsulated exosomes (Gel@ExmodAtf5) in vitro and in vivo for OA treatment.
Main Methods:
- Utilized modified mRNAs (modRNAs) for gene delivery of Atf5.
- Engineered exosomes derived from bone mesenchymal stem cells (ExmodAtf5) to deliver Atf5.
- Encapsulated ExmodAtf5 within a PLGA-PEG-PLGA thermosensitive hydrogel (Gel) for sustained release (Gel@ExmodAtf5).
- Assessed therapeutic effects in vitro and in vivo OA models, including cartilage surface integrity, OARSI scores, osteophytes, and subchondral bone changes.
Main Results:
- Gel@ExmodAtf5 demonstrated significant cytoprotective effects on chondrocytes via ATF5.
- Sustained release of ExmodAtf5 from the hydrogel enhanced therapeutic efficacy.
- In vivo studies showed Gel@ExmodAtf5 preserved cartilage, reduced OA hallmarks (low OARSI scores, fewer osteophytes), and mitigated subchondral bone damage.
- ATF5 and mitochondrial protease ClpP were shown to enhance chondrocyte autophagy via the mTOR/Ulk1 pathway.
Conclusions:
- The combination of ExmodAtf5 and PLGA-PEG-PLGA hydrogel is a highly effective strategy for osteoarthritis treatment.
- Gel@ExmodAtf5 significantly enhances therapeutic efficacy and prolongs exosome release, alleviating OA progression.
- This approach holds promise as a novel therapeutic for managing osteoarthritis by targeting chondrocyte mitochondrial health and ECM homeostasis.
