Alleviation of Aging‐Related Hallmarks in a Mouse Model of Progeria via a Nanoparticle‐Based Artificial Transcription Factor

Abstract The increasing demand for precise and safe modulation of cellular rejuvenation and reprogramming has driven the development of innovative nanotechnologies capable of achieving unprecedented control over cell fate and function. Among these, biomimetic nanoparticles stand out due to their enhanced biocompatibility, improved targeting capabilities, prolonged circulation time, and multifunctionality. These attributes position them as promising tools for advancing drug delivery, personalized medicine, and targeted therapies for various diseases. In this study, a novel nanoparticle‐based artificial transcription factor developed, termed Oct4‐nanoscript, specifically designed to emulate the function of the Oct4 gene. This results support that the Oct4‐nanoscript exhibits high‐affinity DNA binding, efficient nuclear localization, and robust activation of Oct4 target genes. Furthermore, partial reprogramming induced by Oct4‐nanoscript significantly reduced DNA damage and restored key epigenetic marks, hallmarks of cellular aging. In a Hutchinson‐Gilford Progeria Syndrome (HGPS) mouse model, the Oct4‐nanoscript effectively rescued age‐related pathological features and extended lifespan. This non‐viral, stable, and highly specific biomimetic nanoparticle platform for emulating Oct4 gene function presents a promising therapeutic strategy for age‐related diseases, including HGPS. These findings advance the field of regenerative medicine, offering a foundation for developing innovative therapies targeting complex biological challenges.