虽然高剂量的多药化疗已经提高了白血病的存活率，但高危亚型的治疗结果仍然不佳，包括婴儿急性髓系白血病（AML）和急性淋巴细胞白血病（ALL）。因此，为这些患者开发新的更有效的治疗方案是迫切而未满足的临床需求。我们对AML和MLL重排前体B细胞ALL（婴儿ALL）细胞系进行了MRX-2843和BCL-2家族蛋白抑制剂的高通量筛选。建立了一个神经网络模型来correlation ratiometric药物协同作用和靶基因表达。将药物装载到脂质体纳米载体中，评估原发AML细胞的响应。 MRX-2843与venetoclax协同作用，可以在体外减少AML细胞密度。基于药物暴露和靶基因表达的神经网络分类器能够准确预测AML中药物的协同作用和生长抑制。组合单价脂质体药物制剂可以在细胞内提供定义的药物比例，并重新表现出药物的协同作用。在一组基因型多样的原发AML骨髓标本中，协同反应的幅度和频率得以保持和提高。 我们开发了一种纳米尺度的组合药物制剂，利用MERTK酪氨酸激酶的异位表达和对BCL-2家族蛋白的依赖来实现对儿童AML和婴儿ALL细胞的存活的杀伤。我们通过组合药物筛选和纳米尺度制剂的系统性且可推广的方法，证明了在AML中的比例药物传递和协同的细胞杀伤，该结果未来可以扩展到其他药物对或疾病。© 2023。作者许可下，由Springer Science+Business Media，LLC，陆续一部分Springer Nature发表。

Although high-dose, multiagent chemotherapy has improved leukemia survival rates, treatment outcomes remain poor in high-risk subsets, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in infants. The development of new, more effective therapies for these patients is therefore an urgent, unmet clinical need.The dual MERTK/FLT3 inhibitor MRX-2843 and BCL-2 family protein inhibitors were screened in high-throughput against a panel of AML and MLL-rearranged precursor B-cell ALL (infant ALL) cell lines. A neural network model was built to correlate ratiometric drug synergy and target gene expression. Drugs were loaded into liposomal nanocarriers to assess primary AML cell responses.MRX-2843 synergized with venetoclax to reduce AML cell density in vitro. A neural network classifier based on drug exposure and target gene expression predicted drug synergy and growth inhibition in AML with high accuracy. Combination monovalent liposomal drug formulations delivered defined drug ratios intracellularly and recapitulated synergistic drug activity. The magnitude and frequency of synergistic responses were both maintained and improved following drug formulation in a genotypically diverse set of primary AML bone marrow specimens.We developed a nanoscale combination drug formulation that exploits ectopic expression of MERTK tyrosine kinase and dependency on BCL-2 family proteins for leukemia cell survival in pediatric AML and infant ALL cells. We demonstrate ratiometric drug delivery and synergistic cell killing in AML, a result achieved by a systematic, generalizable approach of combination drug screening and nanoscale formulation that may be extended to other drug pairs or diseases in the future.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.