Engineering Mesenchymal Stem Cells for Healthspan-Relevant Applications: Therapeutic Potential, Challenges, and Future Solutions
Highlights What are the main findings? In various clinical trials, largely unmodified mesenchymal stem cell (MSC) therapies have shown limited and inconsistent benefits, highlighting the need for a shift toward MSC products engineered to target specific mechanisms and diseases. Targeted engineering, such as genetic modification, hematopoietic cell E-/L-selectin ligand (HCELL)/CD44 and E-selectin glycoengineering, hypoxic/cytokine preconditioning, biomaterial scaffolding, and MSC-derived extracellular vesicles, may address core limitations of unmodified MSCs by improving homing, persistence, immunomodulation, and resistance to senescence in preclinical models, which may in turn contribute to healthspan-relevant outcomes. What are the implications of the main findings? Disease-matched and combinatorial engineering could establish MSCs as a flexible therapeutic platform for treating age-related diseases and potentially improving healthspan-related outcomes rather than lifespan alone. Clinical translation will depend on standardized manufacturing, validated potency and senescence resistance assays, long-term monitoring of tumorigenicity, and regulatory frameworks suited to aged recipients. Abstract Engineered mesenchymal stem cells (MSCs) have emerged as promising therapeutic platforms for healthspan-relevant applications. As agents of tissue repair and modulators of biological aging, MSCs have been widely studied for their capacity to enhance regeneration, restore immune homeostasis, and reduce chronic inflammation associated with age-related decline. This review examines emerging bioengineering strategies designed to overcome key age-related limitations in MSC homing, survival, and paracrine signaling, which have historically constrained their in vivo efficacy. We discuss major engineering approaches, including genetic modification, surface engineering, metabolic reprogramming, and preconditioning, with particular attention to their contributions to longevity-focused applications. Preclinical studies have demonstrated that engineered MSCs and their extracellular vesicles (EVs) yield measurable improvements in therapeutic performance. Reported benefits include prolonged persistence in inflamed tissues, partial reversal of senescence-associated phenotypes, and modulation of pro-aging inflammatory pathways. While MSC-derived EVs may offer potential safety advantages and could reduce certain risks associated with live-cell administration, this remains to be confirmed in well-controlled clinical studies, and significant challenges persist in terms of manufacturing scalability, cargo consistency, and process standardization. The current literature, which is predominantly preclinical, supports the potential of engineered MSC platforms to improve healthspan-relevant outcomes; direct evidence of healthspan extension in humans is not yet available. However, successful clinical translation will require a standardized manufacturing process to ensure therapeutic safety, reproducibility, and efficacy in age-related conditions.