喜树碱（CPT）是治疗肝细胞癌（HCC）常用的小分子化疗药物之一，但由于严重的毒性和获得性耐药，其临床应用受到限制。据报道，联合化疗基因疗法是对抗耐药性同时使癌细胞对细胞毒性药物敏感的有效策略。因此，我们假设CPT与miR-145联合可以协同抑制肿瘤增殖并增强抗肿瘤活性。乳糖酸（LA）修饰的脂质纳米颗粒（LNPs）被开发用于将CPT和miR-145共同递送至表达脱唾液酸糖蛋白受体的细胞中。 HCC 体外和体内。我们利用CCK8、Western blotting、细胞凋亡和伤口划痕实验在体外评估了miR-145和CPT的协同抗肿瘤作用，并进一步研究了协同抗肿瘤作用的机制。使用二乙基亚硝胺 (DEN)  CCl4 诱导的 HCC 小鼠模型评估肿瘤抑制功效、安全性评估和 MRI 可见能力。LA 修饰改善了货物向 HCC 细胞和组织的靶向递送。 LA-CMGL 介导的 miR-145 和 CPT 共同递送比单独使用 LA-CPT-L 或 LA-miR-145-L 治疗更有效，无论是在体外还是在体内，几乎没有副作用治疗期间。从机制上讲，miR-145可能通过靶向SUMO特异性肽酶1（SENP1）介导的己糖激酶（HK2）SUMO化和糖酵解途径来诱导细胞凋亡，进而使癌细胞对CPT敏感。体外和体内测试证实，负载的 Gd-DOTA 可作为有效的 T1 加权造影剂，用于非侵入性肿瘤检测以及药物递送和生物分布的实时监测。LA-CMGL 介导的 miR 共递送-145 和 CPT 对 HCC 具有协同治疗作用。新型 MRI 可见、主动靶向化疗基因共传递系统用于 HCC 治疗，为未来 HCC 治疗策略的发展提供了科学依据和有用的思路。© 2024。作者。

Camptothecin (CPT) is one of the frequently used small chemotherapy drugs for treating hepatocellular carcinoma (HCC), but its clinical application is limited due to severe toxicities and acquired resistance. Combined chemo-gene therapy has been reported to be an effective strategy for counteracting drug resistance while sensitizing cancer cells to cytotoxic agents. Thus, we hypothesized that combining CPT with miR-145 could synergistically suppress tumor proliferation and enhance anti-tumor activity.Lactobionic acid (LA) modified lipid nanoparticles (LNPs) were developed to co-deliver CPT and miR-145 into asialoglycoprotein receptors-expressing HCC in vitro and in vivo. We evaluated the synergetic antitumor effect of miR-145 and CPT using CCK8, Western blotting, apoptosis and wound scratch assay in vitro, and the mechanisms underlying the synergetic antitumor effects were further investigated. Tumor inhibitory efficacy, safety evaluation and MRI-visible ability were assessed using diethylnitrosamine (DEN) + CCl4-induced HCC mouse model.The LA modification improved the targeting delivery of cargos to HCC cells and tissues. The LA-CMGL-mediated co-delivery of miR-145 and CPT is more effective on tumor inhibitory than LA-CPT-L or LA-miR-145-L treatment alone, both in vitro and in vivo, with almost no side effects during the treatment period. Mechanistically, miR-145 likely induces apoptosis by targeting SUMO-specific peptidase 1 (SENP1)-mediated hexokinase (HK2) SUMOylation and glycolysis pathways and, in turn, sensitizing the cancer cells to CPT. In vitro and in vivo tests confirmed that the loaded Gd-DOTA served as an effective T1-weighted contrast agent for noninvasive tumor detection as well as real-time monitoring of drug delivery and biodistribution.The LA-CMGL-mediated co-delivery of miR-145 and CPT displays a synergistic therapy against HCC. The novel MRI-visible, actively targeted chemo-gene co-delivery system for HCC therapy provides a scientific basis and a useful idea for the development of HCC treatment strategies in the future.© 2024. The Author(s).