Liu Qi, Wang Chun, Zheng Yadan, Zhao Yu, Wang Ying, Hao Jialei, Zhao Xinzhi, Yi Kaikai, Shi Linqi, Kang Chunsheng, Liu Yang
State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, National Demonstration Center for Experimental Chemistry Education, Nankai University, Tianjin, 300071, China.
Key Laboratory of Post-neurotrauma Neuro-repair and Regeneration in Central Nervous System Ministry of Education and Tianjin City, Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Biomaterials. 2020 Nov;258:120275. doi: 10.1016/j.biomaterials.2020.120275. Epub 2020 Aug 7.
The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9 (Cas9) system holds great promise for the cancer gene therapy. However, due to complicated signal networks and various compensatory mechanisms in tumors, adjusting a single molecular pathway has limited effects on cancer treatments. Herein, a virus-like nanoparticle (VLN) was reported as a versatile nanoplatform to co-deliver CRISPR/Cas9 system and small molecule drugs for effective malignant cancer treatment. VLN has a core-shell structure, in which small molecule drugs and CRISPR/Cas9 system are loaded in the mesoporous silica nanoparticle (MSN)-based core, which is further encapsulated with a lipid shell. This structure allows VLN maintaining stable during blood circulation. As reaching tumors, VLN releases the CRISPR/Cas9 system and small molecule drugs in response to the reductive microenvironment, resulting in the synergistic regulation of multiple cancer-associated pathways. By loading a single guide RNA (sgRNA) targeting programmed death-ligand 1 and axitinib, VLN achieved to disrupt multiple immunosuppressive pathways and suppress the growth of melanoma in vivo. More importantly, VLN can co-deliver almost any combination of sgRNAs and small molecule drugs to tumors, suggesting the great potential of VLN as a general platform for the development of advanced combination therapies against malignant tumors.
成簇规律间隔短回文重复序列（CRISPR）相关蛋白9（Cas9）系统在癌症基因治疗方面极具前景。然而，由于肿瘤中复杂的信号网络和各种补偿机制，调节单一分子途径对癌症治疗的效果有限。在此，一种病毒样纳米颗粒（VLN）被报道为一种多功能纳米平台，可共同递送CRISPR/Cas9系统和小分子药物以有效治疗恶性肿瘤。VLN具有核壳结构，其中小分子药物和CRISPR/Cas9系统被负载在基于介孔二氧化硅纳米颗粒（MSN）的核中，该核进一步被脂质壳包裹。这种结构使VLN在血液循环过程中保持稳定。到达肿瘤部位后，VLN会响应还原性微环境释放CRISPR/Cas9系统和小分子药物，从而对多个癌症相关途径进行协同调节。通过负载靶向程序性死亡配体1和阿昔替尼的单向导RNA（sgRNA），VLN在体内实现了破坏多种免疫抑制途径并抑制黑色素瘤生长。更重要的是，VLN可以将几乎任何sgRNA和小分子药物的组合共同递送至肿瘤，这表明VLN作为开发针对恶性肿瘤的先进联合疗法的通用平台具有巨大潜力。
