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Abstract The liver is a vital organ with numerous functions, including metabolic functions, detoxification, and the synthesis of secretory proteins. The increasing prevalence of liver diseases requires the development of effective treatments, models, and regenerative approaches. The field of liver tissue engineering represents a significant advance in overcoming these challenges. In this study, 3D biohybrid constructs were created by combining hepatocyte-like cells (HLCs) derived from patient-specific footprint-free human induced pluripotent stem cells (hiPSCs) and 3D melt-electrospun poly-ε-caprolactone (PCL) scaffolds. First, a differentiation procedure was established to obtain autologous HCLs from hiPSCs reprogrammed from renal epithelial cells using self-replicating mRNA. The obtained cells expressed hepatocyte-specific markers and exhibited important hepatocyte functions, such as albumin synthesis, cytochrome P450 activity, glycogen storage, and indocyanine green metabolism. Biocompatible PCL scaffolds were fabricated by melt-electrospinning and seeded with pre-differentiated hepatoblasts, which uniformly attached to the fibers of the scaffolds and successfully matured into HLCs. The use of patient-specific, footprint-free hiPSC-derived HLCs represents a promising cell source for personalized liver regeneration strategies. In combination with biocompatible 3D scaffolds, this innovative approach has a broader range of applications spanning liver tissue engineering, drug testing and discovery, and disease modeling.