Since the introduction of the mRNA COVID-19 vaccines, ionizable lipid-based mRNA delivery systems have gained attention for their potential applications in immunotherapy and tissue engineering. However, current chemical transfection reagents suffer from low transfection efficiency when transfecting mRNA into certain primary cells and stem cells. To address this, we designed a library of 4,200 lipids of which a panel of 82 potential candidates were synthesized and screened in iPSC-derived MSCs (iMSCs) and human peripheral blood mononuclear cells (PBMCs). Lipids were designed with biodegradable branched tails and a spermine-derived backbone, a structural characteristic of the ToRNAdo™ Nucleic-Acid Delivery System. Cells were transfected with GFP-encoding RNA complexed with each of the candidate lipids. High content imaging analysis showed peak GFP expression 18-24 hours after transfection. Additionally, flow cytometric phenotyping was conducted 24 hours after transfection to assess GFP expression. 45 lipids induced GFP expression in CD14+ monocytes and CD3+ T cells. Over 60 of the novel lipids transfected iMSCs with 70-99% efficiency and 83-95% viability. Our data demonstrate novel polyvalent, ionizable lipids that enable delivery of mRNA into hard-to-transfect cells, including human CD14+ and CD3+ cells. These novel lipids may prove useful in the development of mRNA therapeutics targeting hard-to-transfect cell types.