Yang Yulu, Chen Rui, Gong Yi, Yang Weihu, Li Ke, Fan Wuzhe, Gou Shuangquan, Gao Pengfei, He Tingting, Cai Kaiyong
Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, China.
Department of Pathology, Chongqing Cancer Institute/Hospital, Chongqing, 400030, China.
Biomaterials. 2022 Aug;287:121607. doi: 10.1016/j.biomaterials.2022.121607. Epub 2022 May 31.
Diffuse large B-cell lymphoma (DLBCL) is a systemic hematological malignancy. Herein, through whole exome sequencing (WES), we found that DLBCL genome changes and expression characteristics are associated with various immune cells. Lenalidomide (Len) is a leading candidate for the immunomodulatory treatment of multiple myeloma in the clinic. Inspired by lenalidomide as an immunomodulatory drug for the treatment of multiple myeloma, we constructed a multifunctional nanoplatform with therapeutic and imaging properties for DLBCL by co-loading lenalidomide and dexamethasone (Dex) with upconversion nanoparticles using a GSH-sensitive linker (named as UCNPs-Len-Dex). In vitro cell experiments proved that the UCNPs-Len-Dex had good biocompatibility and obvious antitumor efficacy. UCNPs-Len-Dex also exhibited excellent anti-tumor efficacy and imaging properties in vivo. RNA sequencing showed that UCNPs-Len-Dex targeted and activated the E3 ligase of CRBN, resulting in IKZF1/3 degradation, which inhibited MYC/BCL6-positive DLBCL and maintained the stability of the immune microenvironment. Therefore, this study provided a new monitoring and therapeutic synergetic strategy for DLBCL.
弥漫性大B细胞淋巴瘤（DLBCL）是一种全身性血液系统恶性肿瘤。在此，通过全外显子组测序（WES），我们发现DLBCL基因组变化和表达特征与多种免疫细胞相关。来那度胺（Len）是临床上用于多发性骨髓瘤免疫调节治疗的主要候选药物。受来那度胺作为治疗多发性骨髓瘤的免疫调节药物的启发，我们使用谷胱甘肽敏感连接体将来那度胺和地塞米松（Dex）与上转换纳米颗粒共负载，构建了一种具有治疗和成像特性的多功能纳米平台用于DLBCL（命名为UCNPs-Len-Dex）。体外细胞实验证明UCNPs-Len-Dex具有良好的生物相容性和明显的抗肿瘤疗效。UCNPs-Len-Dex在体内也表现出优异的抗肿瘤疗效和成像特性。RNA测序表明UCNPs-Len-Dex靶向并激活CRBN的E3连接酶，导致IKZF1/3降解，从而抑制MYC/BCL6阳性DLBCL并维持免疫微环境的稳定性。因此，本研究为DLBCL提供了一种新的监测与治疗协同策略。
