Bioengineered MSC-derived extracellular vesicles in intervertebral disc therapeutics: A systematic review

Area of Science:

• Regenerative Medicine
• Biomaterials Science
• Cell Biology

Background:

• Intervertebral disc degeneration (IVDD) is a primary cause of chronic low back pain, with current treatments unable to restore disc function.
• Mesenchymal stem/stromal cell-derived extracellular vesicles (MSC-EVs) show therapeutic potential for IVDD by modulating key degenerative pathways.
• Translation of MSC-EVs is hindered by challenges in isolation, characterization, dosing, and validation.

Purpose of the Study:

• To systematically review bioengineering strategies for enhancing MSC-EV efficacy in the avascular intervertebral disc environment.
• To critically analyze biomaterial-assisted delivery systems for improving MSC-EV therapeutic outcomes in IVDD.

Main Methods:

• Systematic analysis of in vitro, ex vivo, and in vivo studies on primed or engineered MSC-EVs for IVDD.
• Extraction and synthesis of mechanistic pathways modulated by engineered EVs.
• Evaluation of biomaterial carriers for enhanced EV delivery and retention.

Main Results:

• Engineered MSC-EVs consistently attenuated inflammation, oxidative stress, and apoptosis, while restoring extracellular matrix homeostasis.
• Cargo loading, surface modification, and donor-cell priming improved MSC-EV potency, specificity, and yield.
• Biomaterial systems (hydrogels, microspheres, scaffolds) significantly enhanced EV retention, protection, and sustained release, improving therapeutic outcomes.

Conclusions:

• Bioengineered MSC-EVs, particularly when combined with advanced biomaterial carriers, represent a potent, multimodal therapeutic platform for IVDD.
• These hybrid therapeutics offer a promising, next-generation, minimally invasive approach with strong potential for clinical translation.
• This review provides a framework for developing EV-biomaterial therapeutics targeting the underlying biology of IVDD.