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Mesenchymal stem cells (MSCs) are widely used in regenerative medicine and tissue engineering and delivering biological molecules into MSCs has been used to control stem cell behavior. However, the efficient delivery of large biomolecules such as DNA, RNA, and proteins into MSCs using nonviral delivery strategies remains an ongoing challenge. Herein, nanoparticles composed of cationic bioreducible lipid‐like materials (lipidoids) are developed to intracellularly deliver mRNA into human mesenchymal stem cells (hMSCs). The delivery efficacy to hMSCs is improved by adding three excipients including cholesterol, 1,2‐dioleoyl‐sn‐glycero‐3‐phosphoethanolamine (DOPE), and 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐polyethylene glycol (DSPE‐PEG) during lipidoid nanoparticle formulation. Using an optimized lipidoid formulation, Cas9 mRNA and single guide RNA (sgRNA) targeting neuron restrictive silencing factor (NRSF) are delivered to hMSCs, leading to successful neural‐like differentiation as demonstrated by the expression of synaptophysin (SYP), brain‐derived neurotrophic factor (BDNF), neuron‐specific enolase (NSE), and neuron‐specific growth‐associated protein (SCG10). Overall, a synthetic lipid formulation that can efficiently deliver mRNA to hMSCs is identified, leading to CRISPR‐based gene knockdown to facilitate hMSCs transdifferentiation into neural‐like lineage.