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To address these limitations, this study introduces a novel protein-based direct reprogramming platform for the conversion of human dermal fibroblasts into functional osteoblasts using only 2 transcription factors, octamer-binding transcription factor 4 (Oct4) and core-binding factor \u03b2 (Cbf\u03b2), fused to the silkworm-derived cell-penetrating protein, 30Kc19. Genetic fusion with 30Kc19 markedly improves the stability and cellular uptake of both Oct4 and Cbf\u03b2, resulting in recombinant constructs (Oct4-30Kc19 and Cbf\u03b2-30Kc19) that achieve high reprogramming efficiency with negligible cytotoxicity, outperforming plasmid DNA-based methods. The protein-induced osteoblasts (piOBs) exhibit a characteristic osteoblast morphology, express established osteogenic markers, and display a global transcriptomic profile that aligns with key features of primary human osteoblasts. Importantly, transplantation of piOBs into a murine calvarial defect model induces substantial new bone formation, demonstrating in\u00a0vivo therapeutic efficacy. By leveraging the unique cell-permeable and protein-stabilizing properties of 30Kc19, this streamlined 2-factor system represents a potentially safer, more scalable, and clinically feasible strategy for regenerative therapies targeting bone diseases, circumventing the inherent risks associated with viral vectors and genomic integration.<\/jats:p>","DOI":"10.34133\/bmr.0320","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T17:44:16Z","timestamp":1768412656000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":2,"title":["Transgene-Free Direct Osteogenic Reprogramming Using Cell-Permeable Octamer-Binding Transcription Factor 4\/Core-Binding Factor \u03b2 Fusion Proteins"],"prefix":"10.34133","volume":"30","author":[{"given":"Manho","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Biomedical Science, \rKangwon National University, Chuncheon, Republic of 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