Dual-stimuli responsive nanoparticles for co-delivery of small molecules to promote neural differentiation of human iPSCs

Abstract

The differentiation of human induced pluripotent stem cells (hiPSCs) into neural progenitor cells (NPCs) is a promising approach for the treatment of neurodegenerative diseases and regenerative medicine. Dual SMAD inhibition using small molecules has been identified as a key strategy for directing the differentiation of hiPSCs into NPCs by regulating specific cell signaling pathways. However, the conventional culture methods are time-consuming and exhibit the low differentiation efficiency in neural differentiation. The nanocarriers can address these obstacles as an efficient method for the controlled release and accurate delivery of small molecules. In this paper, we developed the calcium phosphate-coated mesoporous silica nanoparticles capable of delivering multiple small molecules, including LDN193189 as a bone morphogenetic protein (BMP) inhibitor and SB431542 as a transforming growth factor (TGF)-beta inhibitor, for direct differentiation of hiPSCs-mediated NPCs. Our results demonstrated that this nanocarrier-mediated small molecule release system not only enhanced the in vitro formation of neural rosettes but also modulated the expression levels of key markers. In particular, it downregulated OCT4, a marker of pluripotency, while upregulating PAX6, a critical marker for neuroectoderm. These finding suggest that this controlled small molecule release system holds significant potential for therapeutic applications in neural development and neurodegenerative diseases.