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

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, conventional culture methods are time-consuming and exhibit low differentiation efficiency in neural differentiation. Nanocarriers can address these obstacles as an efficient platform for the controlled release and accurate delivery of small molecules. In this paper, we developed 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 hiPSC-mediated NPCs. Our results demonstrated that this nanocarrier-mediated small molecule release system not only enhanced the <i>in vitro</i> 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 the neuroectoderm. These findings suggest that this controlled small molecule release system holds significant potential for therapeutic applications in neural development and neurodegenerative diseases.