Non-invasive activation of intratumoural gene editing for improved adoptive T-cell therapy in solid tumours

Chen，Xiaohong1; Wang，Shuang2,3; Chen，Yuxuan1; Xin，Huhu1; Zhang，Shuaishuai1; Wu，Di1; Xue，Yanan1,4; Zha，Menglei5; Li，Hongjun1,6; Li，Kai5; Gu，Zhen1,4,6; Wei，Wei2,3; Ping，Yuan1,6

2023

10.1038/s41565-023-01378-3

Nature Nanotechnology   影响因子和分区

1748-3387

1748-3395

Adoptive T-cell therapy against solid tumours is limited by the apoptosis resistance mechanisms of tumour cells and by the extracellular, immunosuppressive tumour microenvironment. Here we report a temperature-sensitive genome-editing nanodevice that can deliver a Cas9 editor with an external trigger which can be used to edit the genome of tumour cells to reduce resistance to apoptosis and modulate the tumour microenvironment via a mild heating trigger. After local or systemic delivery of Cas9, mild heating is induced by non-invasive near-infrared (NIR) light or focused ultrasound (FUS) to activate Cas9, which initiates simultaneous genome editing of HSP70 (HSPA1A) and BAG3 in tumour cells. This disrupts the apoptotic resistance machinery of the tumour cells against adoptive T cells. At the same time, an NIR- or FUS-induced mild thermal effect reshapes the extracellular tumour microenvironment by disrupting the physical barriers and immune suppression. This facilitates the infiltration of adoptive T cells and enhances their therapeutic activity. Mild thermal Cas9 delivery is demonstrated in different murine tumour models which mimic a range of clinical indications, including a tumour model based on humanized patient-derived xenografts. As a result, the non-invasive thermal delivery of Cas9 significantly enhances the therapeutic efficacies of tumour-infiltrating lymphocytes and chimeric antigen receptor T and shows potential for clinical application.

SCI ; EI

英语

NI论文

其他

National Key Research and Development Program of China[2021YFA0909900] ; National Natural Science Foundation of China["82073779","32261143727","U2001224","U21A2097"] ; Natural Science Foundation of Zhejiang Province (Distinguished Young Scholar Program)[LR21H300002]

Science & Technology - Other Topics ; Materials Science

Nanoscience & Nanotechnology ; Materials Science, Multidisciplinary

WOS:000987963300001

NATURE PORTFOLIO

20232014107084

Cell death ; Infrared devices ; Tumors

Biological Materials and Tissue Engineering:461.2 ; Biology:461.9 ; Immunology:461.9.1

2-s2.0-85159370213

Scopus

1.College of Pharmaceutical Sciences,Zhejiang University,Hangzhou,China
2.State Key Laboratory of Biochemical Engineering,Institute of Process Engineering,Chinese Academy of Sciences,Beijing,China
3.School of Chemical Engineering,University of Chinese Academy of Sciences,Beijing,China
4.Department of General Surgery,Sir Run Run Shaw Hospital,School of Medicine,Zhejiang University,Hangzhou,China
5.Department of Biomedical Engineering,Southern University of Science and Technology,Shenzhen,China
6.Liangzhu Laboratory,Zhejiang University Medical Center,Hangzhou,China

Chen，Xiaohong,Wang，Shuang,Chen，Yuxuan,et al. Non-invasive activation of intratumoural gene editing for improved adoptive T-cell therapy in solid tumours[J]. Nature Nanotechnology,2023,18(8):933-944.

Chen，Xiaohong.,Wang，Shuang.,Chen，Yuxuan.,Xin，Huhu.,Zhang，Shuaishuai.,...&Ping，Yuan.(2023).Non-invasive activation of intratumoural gene editing for improved adoptive T-cell therapy in solid tumours.Nature Nanotechnology,18(8),933-944.

Chen，Xiaohong,et al."Non-invasive activation of intratumoural gene editing for improved adoptive T-cell therapy in solid tumours".Nature Nanotechnology 18.8(2023):933-944.