纳米载体递送CRISPRa定向诱导T细胞浸润用于增强免疫检查点抗体疗效的研究

批准号:
81901875
项目类别:
青年科学基金项目
资助金额:
21.0 万元
负责人:
鲁紫东
依托单位:
学科分类:
H2808.纳米医学
结题年份:
2022
批准年份:
2019
项目状态:
已结题
项目参与者:
--
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中文摘要
免疫检查点疗法是极具潜力的肿瘤疗法,但其临床响应率较低。增加实体瘤的T细胞浸润可提高其响应率,然而,临床缺乏定向诱导T细胞浸润的方法。CRISPRa是基于CRISPR的基因激活系统,可在不编辑基因组的前提下,激活特定基因表达。本项目拟通过纳米载体递送CRISPRa特异性地激活肿瘤表达趋化因子,定向诱导T细胞向实体瘤浸润。申请人前期通过阳离子脂质辅助的纳米颗粒(CLAN)递送CRISPR调控炎症因子表达(Nat Commun,2018),预实验也证明CRISPRa可激活趋化因子的表达。本项目拟在此基础上,选择黑色素瘤作为模型,通过改进CLAN的聚合物和脂质组分,筛得高效递送CRISPRa的纳米颗粒;同时构建在黑色素瘤特异性表达的CRISPRa系统,精准激活黑色素瘤细胞表达趋化因子,从而定向诱导T细胞浸润;项目将联合靶向PD-1或PD-L1的抗体进行治疗,为提高免疫检查点疗法响应率提供新策略。
英文摘要
Immune checkpoint blockade therapy is one of the most promising therapeutics of cancer, but its clinical response rate is low. Studies have demonstrated that increasing the infiltration of T cells into solid tumors can significantly enhance the response rate of immune checkpoint blockade therapy. However, there are still no effective methods of facilitating T cell oriented infiltration into solid tumors in clinic. CRISPRa (CRISPR activation) is a CRISPR-based regulation system of gene expression, which can activate the expression of specific gene precisely without editing the genome. This project intends to deliver CRISPRa via nanoparticles to specifically activate tumor cells to express chemokines (CXCL9, CXCL10 and CXCL11), thereby facilitating T cell oriented infiltration into solid tumors. The applicant has already regulated the expression of inflammatory cytokines by cationic lipid-assisted nanoparticles (CLAN)-delivered CRISPR/Cas9 in my previous work (Nat. Commun., 2018). Preliminary data has also demonstrated that CLAN-mediated delivery of CRISPRa can activate the expression of chemokines (CXCL9, CXCL10 and CXCL11) by melanoma cells. Based on the above works we have done, the project will select melanoma as the cancer model, whose clinical response rate to immune checkpoint therapy is relatively low. The project will screen out a CLAN that can efficiently deliver CRISPRa into melanoma by regulating the formulation (including polymers and lipids) of CLAN. Additionally, by constructing a melanoma-specific promoter-driven CRISPRa system, we will specifically activate the expression of chemokines (CXCL9, CXCL10 and CXCL11) in melanoma cells, thereby facilitating T cell oriented infiltration into melanoma. The project will combine the blocking antibodies of PD-1 or PD-L1 to enhance the immune checkpoint blockade therapy. The project will provide an efficient and safe strategy to enhance the response rate of the immune checkpoint blockade therapy.
本项目针对免疫检查点疗法面临T细胞浸润不足导致的临床响应率较低的问题,致力于构建阳离子脂质辅助纳米载体(CLAN)递送CRISPRa等工具特异性地激活或者上调肿瘤内趋化因子的表达,定向诱导T细胞向实体瘤浸润,增强免疫检查点抗体的治疗效果。主要成果包括:(1)通过筛选的CLAN纳米颗粒递送驱动CRISPRa系统(dCas9-SAM)组分在黑色素瘤内特异性表达的质粒,特异性地在黑色素瘤内上调CXCL9、CXCL10和CXCL11三种趋化因子的表达,实现了定向诱导T细胞或者CAR-T细胞向黑色素瘤内的浸润,并联合免疫检查点抗体anti-PD-1或者anti-PD-L1进行黑色素瘤治疗,提高免疫检查点抗体疗法的响应率。(2)构建了能够在黑色素瘤和多种肿瘤内特异性表达的基因纳米药物NPTyr-C9AP和NPSur-C9AP,实现了在肿瘤内特异性表达CXCL9增强T细胞浸润的同时,表达免疫检查点抗体anti-PD-L1 scFv,产生了协同的抗肿瘤免疫效应。(3)利用CLAN协同递送靶向SIRPα的siRNA(siSIRPα)和STING激动剂(cGAMP),或者CD155 siRNA等策略,诱导了增强的抗肿瘤免疫反应。(4)设计同步递送自身抗原肽和CRISPR-Cas9核酸药物的CLAN,将树突状细胞(DC)重编程成耐受表型,重建体内特异性免疫耐受, 治疗自身免疫性疾病。本项目研究的肿瘤特异性基因激活或表达的纳米载药系统,为解决实体瘤T细胞浸润不足,提高肿瘤免疫疗法效果提供了新的策略和技术支持。通过筛选递送到肿瘤细胞和不同免疫细胞的最佳纳米颗粒通过对免疫细胞功能干预,为肿瘤、自身免疫病等疾病的治疗提供潜在高效、安全、易规模化的疗法。本项目研究的成果在ACS Applied Materials & Interfaces、Biomaterials science和Advanced Drug Delivery Reviews等高水平SCI刊物上发表论文6篇,申请发明专利1项,完成了预期的目标。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
DOI:10.1016/j.addr.2019.11.005
发表时间:2019-11
期刊:Advanced drug delivery reviews
影响因子:16.1
作者:Cong‐Fei Xu;Guojun Chen;Yingli Luo;Yue Zhang;Gui Zhao;Zi-Dong Lu;A. Czarna;Zhen Gu;Jun Wang-Jun-Wa
通讯作者:Cong‐Fei Xu;Guojun Chen;Yingli Luo;Yue Zhang;Gui Zhao;Zi-Dong Lu;A. Czarna;Zhen Gu;Jun Wang-Jun-Wa
An All-in-One Nanomedicine Consisting of CRISPR-Cas9 and an Autoantigen Peptide for Restoring Specific Immune Tolerance
一种由 CRISPR-Cas9 和自身抗原肽组成的一体化纳米药物,用于恢复特异性免疫耐受
DOI:10.1021/acsami.0c10885
发表时间:2020
期刊:ACS Applied Materials & Interfaces
影响因子:9.5
作者:Ying-Li Luo;Li-Fang Liang;Yun-Jiu Gan;Jing Liu;Yue Zhang;Ya-Nan Fan;Gui Zhao;Anna Czarna;Zi-Dong Lu;Xiao-Jiao Du;Song Shen;Cong-Fei Xu;Zhe-Xiong Lian;Jun Wang
通讯作者:Jun Wang
Co-delivery of phagocytosis checkpoint silencer and stimulator of interferon genes agonist for synergetic cancer immunotherapy
吞噬检查点沉默剂和干扰素基因激动剂刺激剂的联合递送用于协同癌症免疫治疗
DOI:--
发表时间:2021
期刊:ACS Applied Materials & Interfaces
影响因子:9.5
作者:Zi-Dong Lu;Yi-Fang Chen;Song Shen;Cong-Fei Xu;Jun Wang
通讯作者:Jun Wang
Dually regulating the proliferation and the immune microenvironment of melanoma via nanoparticle-delivered siRNA targeting onco-immunologic CD155
通过纳米颗粒递送的 siRNA 靶向肿瘤免疫 CD155 双重调节黑色素瘤的增殖和免疫微环境
DOI:10.1039/d0bm01420f
发表时间:2020
期刊:Biomaterials Science
影响因子:6.6
作者:Yan Wang;Ying-Li Luo;Yi-Fang Chen;Zi-Dong Lu;Yue Wang;Anna Czarna;Song Shen;Cong-Fei Xu;Jun Wang
通讯作者:Jun Wang
Delivery of mRNA for regulating functions of immune cells.
传递 mRNA 以调节免疫细胞的功能
DOI:10.1016/j.jconrel.2022.03.033
发表时间:2022-05
期刊:Journal of controlled release : official journal of the Controlled Release Society
影响因子:--
作者:Shi J;Huang MW;Lu ZD;Du XJ;Shen S;Xu CF;Wang J
通讯作者:Wang J
基于CRISPR激活的纳米药物定向诱导T细胞浸润增强肿瘤免疫治疗的研究
- 批准号:--
- 项目类别:省市级项目
- 资助金额:10.0万元
- 批准年份:2019
- 负责人:鲁紫东
- 依托单位:
国内基金
海外基金
