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

Intervertebral disc degeneration (IVDD) is a major contributor to chronic low back pain, representing a significant global health burden. Mesenchymal stem/stromal cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free therapeutic strategy, with preclinical evidence demonstrating their ability to modulate inflammation, oxidative stress, apoptosis, senescence, and extracellular matrix (ECM) degradation. However, several challenges limit translation, including inconsistent EV isolation methods, incomplete mechanistic characterization, lack of standardized dosing, and limited long-term or large-animal validation. Bioengineering of EVs can contribute to overcome some of these limitations, namely improving EV bioactivity, controlling cargo composition, and enabling targeted delivery. This systematic review synthetizes bioengineering strategies aimed at improving the efficacy of MSC-EVs in the avascular disc environment. In vitro, ex vivo, and in vivo studies investigating primed or engineered MSC-EVs for IVDD were systematically analyzed. MSC-EVs consistently attenuated pro-inflammatory signaling, reduced oxidative stress, limited apoptosis, pyroptosis, and ferroptosis, and restored ECM homeostasis. Mechanistic pathways activated by engineered EVs were extracted and critically synthesized. Engineering strategies, including cargo loading, surface modification, and donor-cell priming, enhanced EV potency, specificity, and yield. Biomaterial-assisted delivery systems, such as injectable hydrogels, microspheres, and decellularized matrix scaffolds, improved EV retention, protection, and sustained release within the IVD, markedly enhancing therapeutic outcomes compared to direct injection. Overall, MSC-EVs represent a robust, multimodal therapeutic platform capable of targeting the core degenerative mechanisms of IVDD. When combined with bioengineering strategies and advanced biomaterial carriers, MSC-EVs offer a promising next-generation, minimally invasive approach with strong potential for clinical translation in IVDD. STATEMENT OF SIGNIFICANCE: Intervertebral disc degeneration (IVDD) remains a major cause of disability, and current therapies fail to restore disc structure or function. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) represent a promising cell-free therapeutic approach; however, their mechanism-of-action, engineering potential, and biomaterial-based delivery strategies have not been comprehensively evaluated. This systematic review is the first to integrate evidence on native, primed, and engineered MSC-EVs while critically analyzing biomaterial-assisted delivery systems that enhance EV retention, protection, and controlled release within the avascular disc. By synthesizing mechanistic pathways, evaluating engineering strategies, and identifying key translational challenges in isolation and dosing, this work provides a framework for developing next-generation EV-biomaterial hybrid therapeutics targeting the underlying biology of IVDD.