Engineered Stem Cell Clusters for Extracellular Vesicles-Mediated Gene Delivery to Rejuvenate Chondrocytes and...

Area of Science:

• Biomedical Engineering
• Regenerative Medicine
• Gene Therapy

Background:

• Osteoarthritis (OA) gene therapy faces challenges with direct miRNA delivery, including inactivation, low transfection efficiency, and short half-life.
• Mesenchymal stem cells (MSCs) offer potential as a gene delivery platform, but efficient and sustained delivery of therapeutic agents is crucial.

Purpose of the Study:

• To develop a novel gene therapy strategy for osteoarthritis using engineered MSCs-derived extracellular vesicles (EVs) for sustained therapeutic miRNA delivery.
• To evaluate the efficacy of miRNA-874-3p delivered via engineered MSCs and EVs in alleviating OA-induced damage in vitro and in vivo.

Main Methods:

• Engineered bone marrow mesenchymal stem cells (BMSCs) transfected with miRNA-874-3p and an exosome-targeting motif.
• BMSCs seeded onto hydrogel microspheres to create a BMSC^motif+miR874/MS system for sustained gene delivery.
• In vitro assessment of chondrocyte protection and chondrogenesis promotion; in vivo evaluation in a rat OA model.

Main Results:

• Engineered BMSCs sustained the delivery of miRNA-874-3p via EVs, rejuvenating chondrocytes by downregulating the NF-κB pathway and promoting chondrogenesis.
• In vivo studies demonstrated prolonged retention of engineered BMSCs and effective delivery of miRNA-874-3p to articular cartilage.
• The BMSC^motif+miR874/MS system significantly alleviated cartilage degeneration in a rat OA model.

Conclusions:

• EVs-mediated gene delivery using engineered MSCs provides a viable, sustained platform for miRNA-based osteoarthritis therapy.
• This approach presents a promising, non-surgical alternative for osteoarthritis treatment, enhancing therapeutic gene delivery efficiency and duration.