Abstract Stem cell biology, which orchestrates embryogenesis, influences aging, and holds promise for revolutionary therapies, represents a central thread in human health. This underscores the pressing need for advanced delivery technologies to facilitate both research progress and clinical translation. Here, we harness coacervates-regarded as protocells during evolution-to develop a pioneering delivery platform. We identified a mammalian endogenous protein that encapsulates diverse nucleic acids through liquid-liquid phase separation (LLPS), forming protein-based coacervates. These coacervates exhibit superior mRNA encapsulation capacity, efficient cellular internalization, robust cytoplasmic cargo release, and broad compatibility across multiple cell types -including primary immune cells and stem cells. The resulting platform, named ProteanFect, supports diverse genetic cargoes for versatile gene manipulation strategies. ProteanFect demonstrated high versatility and efficiency across key stem cell types, including hematopoietic stem cells (HSCs), human embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs) derived from diverse somatic sources such as PBMCs, urine, and adipocytes. It efficiently enabled gene overexpression and knockout through the delivery of mRNA or Cas9 RNP complexes. In a key demonstration of its therapeutic potential for hematological disorders, ProteanFect achieved approximately 80% allele modification at the BCL11A locus in HSCs, a strategy aimed at reactivating fetal hemoglobin to treat hemoglobinopathies, with no detectable off-target editing. Furthermore, the platform facilitated precise genetic correction by delivering prime editing tools into PBMC-derived iPSCs, achieving approximately 55% precise base substitution with high cell viability. In summary, ProteanFect constitutes a versatile, safe, and efficient non-viral platform that operates without synthetic lipids or electroporation. By enabling robust transient expression of reprogramming and gene-editing cargo without genomic integration, it provides a safer and more controllable pathway for cellular reprogramming, iPSC generation, and the development of next-generation cell therapies. Citation Format: Peipei Zhu, Manman Lu, Qing Zhang, Renxia Zhang, Lihong Jiang, Xiaowen Fei, Xiaofei Gao. The first coacervate based delivery system for efficient and safe genetic engineering in stem cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3019.
Zhu et al. (Fri,) studied this question.