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Next-generation bone marrow cell (BMC) therapies are evolving to address longstanding translational challenges in regenerative cardiology by shifting from conventional cell transplantation toward precision-engineered repair systems. Although early approaches using bone marrow-derived mononuclear cells and mesenchymal stem cells demonstrated safety, clinical efficacy remained limited, with modest improvements in left ventricular ejection fraction and inconsistent long-term outcomes. These clinical limitations are largely attributed to poor cell retention, reduced survival within the ischemic microenvironment, and diminished potency of autologous cells. To overcome these barriers, current research focuses on genetic enhancement of BMCs. Key targets include the SDF-1/CXCR4 axis to improve homing and Akt signaling to enhance resistance to apoptosis, utilizing advanced tools such as modified mRNA and CRISPR/Cas9 to enable precise modulation of regenerative pathways. While ongoing clinical studies highlight the translational potential of these approaches, overcoming limited clinical efficacy remains the primary benchmark for the field. CLINICAL RELEVANCE STATEMENT: By combining gene therapy and bioengineering, this next-generation approach overcomes the critical hurdles of poor cell survival and low retention that have historically limited the success of standard bone marrow cell therapies in ischemic hearts. Clinically, this integrated strategy offers a more potent, disease-modifying treatment capable of driving robust cardiac regeneration, reducing infarct size, and ultimately preventing the progression of end-stage heart failure.