原发性骨髓纤维化（PMF）是一种严重的骨髓增生性肿瘤，其特征是低分化的巨核母细胞和逐渐加重的骨髓纤维化。尽管一种靶向Aurora激酶A（AURKA）的小分子抑制剂MLN8237已经被批准用于高危PMF患者的分化治疗临床试验，但其靶外效应导致了部分缓解和严重的并发症。在这里，我们报告了一种双重靶向治疗剂（rLDL-MLN），具有巨大的临床转化潜力，可用于PMF疾病的分化治疗。特别是，再生低密度脂蛋白（rLDL）纳米载体和负载的MLN8237分别通过LDL受体和细胞内AURKA主动靶向恶性造血干/祖细胞（HSPC）。与自由MLN8237相比，rLDL-MLN有效地抑制了PMF细胞系和异常HSPC的增殖，并显著诱导它们的分化，同时防止红细胞和巨核细胞从异常HSPC中形成。令人惊讶的是，即使剂量比自由MLN8237低1500倍（0.01mg/kg），rLDL-MLN仍然表现出更有效的治疗效果，使PMF小鼠几乎清除了爆发细胞。更重要的是，在有效剂量下，rLDL-MLN促进了造血恢复，没有任何毒副作用，在靶向PMF患者的分化治疗中具有巨大的潜力。版权所有©2023 Elsevier B.V. 发布。

Primary myelofibrosis (PMF) is a severe myeloproliferative neoplasm that is characterized by low-differentiation megakaryoblasts and progressive bone marrow fibrosis. Although an Aurora kinase A (AURKA) targeting small-molecule inhibitor MLN8237 has been approved in clinical trials for differentiation therapy of high-risk PMF patients, its off-target side effects lead to a partial remission and serious complications. Here, we report a dual-targeting therapy agent (rLDL-MLN) with great clinical translation potential for differentiation therapy of PMF disease. In particular, the reconstituted low-density lipoprotein (rLDL) nanocarrier and the loaded MLN8237 can actively target malignant hematopoietic stem/progenitor cells (HSPCs) via LDL receptors and intracellular AURKA, respectively. In contrast to free MLN8237, rLDL-MLN effectively prohibits the proliferation of PMF cell lines and abnormal HSPCs and significantly induces their differentiation, as well as prevents the formation of erythrocyte and megakaryocyte colonies from abnormal HSPCs. Surprisingly, even at a 1500-fold lower dosage (0.01 mg/kg) than that of free MLN8237, rLDL-MLN still exhibits a much more effective therapeutic effect, with the PMF mice almost clear of blast cells. More importantly, rLDL-MLN promotes hematological recovery without any toxic side effects at the effective dosage, holding great promise in the targeted differentiation therapy of PMF patients.Copyright © 2023. Published by Elsevier B.V.