Liu Shuhan, Liu Ji, Li Haisong, Mao Kuirong, Wang Haorui, Meng Xiandi, Wang Jialiang, Wu Chenxi, Chen Hongmei, Wang Xin, Cong Xiuxiu, Hou Yue, Wang Ye, Wang Ming, Yang Yong-Guang, Sun Tianmeng
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China; National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China; Cancer Center, The First Hospital, Jilin University, Changchun, Jilin, China.
Beijing National Laboratory for Molecular Science, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry Chinese Academy of Sciences (ICCAS), Beijing, China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
Biomaterials. 2022 Aug;287:121645. doi: 10.1016/j.biomaterials.2022.121645. Epub 2022 Jun 22.
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a high mortality rate. Immunotherapy has achieved promising clinical results in multiple cancers, but shows unsatisfactory outcome in GBM patients, and poor drug delivery across the blood-brain barrier (BBB) is believed to be one of the main limitations that hinder the therapeutic efficacy of drugs. Herein, a new cationic lipid nanoparticle (LNP) that can efficiently deliver siRNA across BBB and target mouse brain is prepared for modulating the tumor microenvironment for GBM immunotherapy. By designing and screening cationic LNPs with different ionizable amine headgroups, a lipid (named as BAMPA-O16B) is identified with an optimal acid dissociation constant (pKa) that significantly enhances the cellular uptake and endosomal escape of siRNA lipoplex in mouse GBM cells. Importantly, BAMPA-O16B/siRNA lipoplex is highly effective to deliver siRNA against CD47 and PD-L1 across the BBB into cranial GBM in mice, and downregulate target gene expression in the tumor, resulting in synergistically activating a T cell-dependent antitumor immunity in orthotopic GBM. Collectively, this study offers an effective strategy for brain targeted siRNA delivery and gene silencing by optimizing the physicochemical property of LNPs. The effectiveness of modulating immune environment of GBM could further be expanded for potential treatment of other brain tumors.
多形性胶质母细胞瘤（GBM）是最常见且侵袭性最强的原发性脑肿瘤，死亡率很高。免疫疗法在多种癌症中取得了有前景的临床结果，但在GBM患者中效果并不理想，而药物难以穿过血脑屏障（BBB）被认为是阻碍药物治疗效果的主要限制因素之一。在此，制备了一种新型阳离子脂质纳米颗粒（LNP），其能够有效将小干扰RNA（siRNA）转运穿过血脑屏障并靶向小鼠脑，用于调节GBM免疫治疗的肿瘤微环境。通过设计和筛选具有不同可电离胺头基的阳离子LNP，鉴定出一种脂质（命名为BAMPA-O16B），其具有最佳酸解离常数（pKa），可显著增强小鼠GBM细胞中siRNA脂质体复合物的细胞摄取和内体逃逸。重要的是，BAMPA-O16B/siRNA脂质体复合物能够高效地将针对CD47和程序性死亡受体配体1（PD-L1）的siRNA穿过血脑屏障递送至小鼠颅内GBM，并下调肿瘤中的靶基因表达，从而协同激活原位GBM中T细胞依赖性抗肿瘤免疫。总体而言，本研究通过优化LNP的物理化学性质，为脑靶向siRNA递送和基因沉默提供了一种有效策略。调节GBM免疫环境的有效性可进一步扩展用于其他脑肿瘤的潜在治疗。
