Triterpenoids-templated self-assembly nanosystem for biomimetic delivery of CRISPR/Cas9 based on the synergy of TLR-2 and ICB to enhance HCC immunotherapy  

作　　者：Bing-Chen Zhang Chun-Mei Lai Bang-Yue Luo Jing-Wei Shao 

机构地区：[1]Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy,College of Chemistry,Fuzhou University,Fuzhou 350116,China [2]Department of Laboratory Medicine,Dongguan Institute of Clinical Cancer Research,the Tenth Affiliated Hospital of Southern Medical University(Dongguan People’s Hospital),Dongguan 523058,China [3]College of Materials and Chemical Engineering,MinjiangUniversity,Fuzhou,350108,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第7期3205-3217,共13页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.82172767);the External Cooperation Research Programs of Science and Technology Department Foundation of Fujian Province,China(No.2023I0038).

摘　　要：Combination immunotherapy has shown promising potential for enhancing the objective response rate compared to immune checkpoint blockade(ICB)monotherapy.However,combination therapy with multi-drugs is limited by the different properties of the agents and inconsistent synergistic targeted delivery.Herein,based on a universal triterpene template and the anticancer active agent ursolic acid(UA),a cytomembrane-coated biomimetic delivery nanoplatform(UR@M)prepared by the selfassembly of a PD-L1 targeted CRISPR/Cas9 system and UA was designed for hepatocellular carcinoma(HCC)treatment.UR@M showed enhanced tumor accumulation in vivo with homologous tumor targeting,and CRISPR in the nanosystem exhibited potent gene-editing efficiency of 76.53% in vitro and 62.42% in vivo with no off-target effects.UA activated the natural immune system through the TLR-2-MyD88-TRAF6 pathway,which synergistically enhanced the proliferation of natural killer cells and dendritic cells and realized excellent immune cytotoxic T cell infiltration by combining with the ICB of PD-L1.The strategy of work along both lines based on innate immune and adaptive immunity displayed a significant effect in tumor regression.Overall,the UA-templated strategy“killed three birds with one stone”by establishing a self-assembly nanosystem,inducing tumor cell death,and promoting synergistic immunostimulation for HCC treatment.

关 键 词：Ursolic acid SELF-ASSEMBLY Biomimetic nanoplatform Hepatocellular carcinoma CRISPR/Cas9 Immune checkpoint blockade Gene therapy IMMUNOTHERAPY 

分 类 号：R392[医药卫生—免疫学] R318[医药卫生—基础医学]