Optimized lipid nanoparticles enable effective CRISPR/Cas9-mediated gene editing in dendritic cells for enhanced immunotherapy.

Kuirong MAO; Huizhu TAN; Xiuxiu CONG; Ji LIU; Yanbao XIN; Jialiang WANG; Meng GUAN; Jiaxuan LI; Ge ZHU; Xiandi MENG; Guojiao LIN; Haorui WANG; Jing HAN; Ming WANG; Yong-Guang YANG; Tianmeng SUN

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Optimized lipid nanoparticles enable effective CRISPR/Cas9-mediated gene editing in dendritic cells for enhanced immunotherapy.

Author: Kuirong MAO ¹ ; Huizhu TAN ¹ ; Xiuxiu CONG ¹ ; Ji LIU ² ; Yanbao XIN ¹ ; Jialiang WANG ¹ ; Meng GUAN ¹ ; Jiaxuan LI ¹ ; Ge ZHU ¹ ; Xiandi MENG ¹ ; Guojiao LIN ¹ ; Haorui WANG ¹ ; Jing HAN ¹ ; Ming WANG ² ; Yong-Guang YANG ¹ ; Tianmeng SUN ¹
Author Information

1. Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun 130061, China.
2. Beijing National Laboratory for Molecular Science, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry Chinese Academy of Sciences (ICCAS), Beijing 100190, China.
Publication Type:Journal Article
Keywords: CRISPR/Cas9; Cholesterol density; Dendritic cells; Gene editing; Immune-related diseases; Immunotherapy; Lipid nanoparticles; PD-L1
From: Acta Pharmaceutica Sinica B 2025;15(1):642-656
CountryChina
Language:English
Abstract: Immunotherapy has emerged as a revolutionary approach to treat immune-related diseases. Dendritic cells (DCs) play a pivotal role in orchestrating immune responses, making them an attractive target for immunotherapeutic interventions. Modulation of gene expression in DCs using genome editing techniques, such as the CRISPR-Cas system, is important for regulating DC functions. However, the precise delivery of CRISPR-based therapies to DCs has posed a significant challenge. While lipid nanoparticles (LNPs) have been extensively studied for gene editing in tumor cells, their potential application in DCs has remained relatively unexplored. This study investigates the important role of cholesterol in regulating the efficiency of BAMEA-O16B lipid-assisted nanoparticles (BLANs) as carriers of CRISPR/Cas9 for gene editing in DCs. Remarkably, BLANs with low cholesterol density exhibit exceptional mRNA uptake, improved endosomal escape, and efficient single-guide RNA release capabilities. Administration of BLAN_mCas9/gPD-L1 results in substantial PD-L1 gene knockout in conventional dendritic cells (cDCs), accompanied by heightened cDC1 activation, T cell stimulation, and significant suppression of tumor growth. The study underscores the pivotal role of cholesterol density within LNPs, revealing potent influence on gene editing efficacy within DCs. This strategy holds immense promise for the field of cancer immunotherapy, offering a novel avenue for treating immune-related diseases.