The accelerating trend of global population aging poses unprecedented challenges to healthcare systems worldwide, driving an urgent need for innovative and safe therapeutic strategies to address age-related degenerative diseases. Although mesenchymal stem cells (MSCs) have shown broad application potential in clinical trials, their use is associated with significant risks, including tumorigenicity. This underscores the necessity to explore alternative, cell-free therapies that retain therapeutic efficacy while minimizing such risks. Mesenchymal stem cell-derived exosomes (MSC-exosomes) have emerged as a promising candidate in this regard, offering significant potential in mitigating tissue dysfunction, modulating inflammation, and promoting regeneration in aging-associated pathologies. This comprehensive review aims to elaborate on the bioactive composition of MSC-exosomes, outline recent advances in their preparation and application technologies, and critically evaluate their therapeutic efficacy in various aging-related degenerative conditions. MSC-exosomes are nanoscale extracellular vesicles (40-100 nm) enriched with a diverse cargo of lipids, proteins, and nucleic acids inherited from their parent cells. Their lipid bilayer membrane contains specialized components such as ganglioside GM1, which contributes to neuroprotection and exosome bioregulation. Proteomic analyses reveal that MSC-exosomes carry functional proteins, including growth factors, immune modulators, and tissue repair mediators, as well as the 20S proteasome complex capable of degrading misfolded proteins, a hallmark of many age-related diseases. Furthermore, MSC-exosomes are loaded with regulatory nucleic acids, particularly microRNAs (e.g., miR-146a, miR-let-7 family) and long non-coding RNAs (e.g., MALAT1, FENDRR), which collectively modulate inflammatory pathways, cellular senescence, oxidative stress, and regenerative responses. Importantly, the cargo profile of MSC-exosomes is highly dependent on their cellular origin, leading to significant compositional and functional heterogeneity. For instance, bone marrow-derived MSC-exosomes are rich in regeneration-related proteins, adipose tissue-derived exosomes are abundant in antioxidant proteins, and umbilical cord-derived exosomes highly express factors that promote wound healing. This source-dependent variation underpins the distinct functional properties and potential therapeutic specializations of different MSC-exosome populations. The review systematically details the technological foundations for MSC-exosome applications, covering isolation methods (e.g., ultracentrifugation, size-exclusion chromatography, microfluidic platforms), storage optimization (using cryoprotectants like trehalose and appropriate buffer systems), and delivery strategies (including systemic administration, localized injection, and biomaterial-based carriers such as hydrogels and microneedles). Advanced culture systems, notably three-dimensional (3D) scaffolds, enhance exosome yield and bioactivity compared to conventional 2D cultures. These advancements collectively establish a relatively complete technical pipeline for exosome production, from purification and preparation to storage and delivery, providing a solid foundation for the future clinical application of MSC-exosomes in treating aging-related degenerative diseases. Preclinical and emerging clinical evidence highlights the therapeutic potential of MSC-exosomes across multiple degenerative disease models. In neurodegenerative disorders, such as Alzheimer′s and Parkinson′s diseases, MSC-exosomes mitigate neuroinflammation, reduce amyloid-β and α-synuclein accumulation, and promote neuronal survival and synaptic repair. In bone degenerative conditions like osteoporosis and osteoarthritis, they enhance osteogenic differentiation, suppress bone resorption, and attenuate cartilage degradation through modulation of inflammatory and anabolic signaling pathways. For cardiovascular and cerebrovascular diseases, including atherosclerosis, ischemic stroke, and heart failure, MSC-exosomes improve vascular endothelial function, stimulate angiogenesis, reduce oxidative stress, and ameliorate fibrotic remodeling. In conclusion, MSC-exosomes hold immense clinical potential as a versatile and potent cell-free therapeutic tool, particularly in addressing the core inflammatory processes underlying aging and degenerative diseases. Evidence confirms the strong association between cellular signaling, chronic inflammation (″inflammaging″), and age-related pathology. The emerging therapeutic paradigm of ″inflammation resolution,″ an active and programmed process, suggests that multi-faceted agents may be more effective than single-target anti-inflammatory drugs. As carriers of ″youthful signals″, MSC-exosomes with their rich cargo of bioactive proteins, miRNAs, and lncRNAs can orchestrate a comprehensive, multi-level modulation of inflammatory responses, offering a novel possibility for treating aging-related conditions based on the principle of inflammation resolution. They are thus emerging as a promising next-generation tool in regenerative medicine. However, their path to clinical translation is impeded by several challenges, including a lack of systematic large-scale clinical trials, product heterogeneity due to variable MSC sources, the absence of unified quality control standards and dosing regimens, and technical immaturity in scalable manufacturing processes. Therefore, future progress hinges on robust clinical validation and targeted preclinical research that addresses these translational hurdles. With continued refinement in standardization, production, and delivery, MSC-exosomes possess substantial promise for transforming the therapeutic landscape for the aging population by decelerating degenerative processes and restoring tissue homeostasis.
LIU et al. (Thu,) studied this question.