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Dual‐Locking Nanoparticles Disrupt the PD‐1/PD‐L1 Pathway for Efficient Cancer Immunotherapy
Author(s) -
Zhang Zhanzhan,
Wang Qixue,
Liu Qi,
Zheng Yadan,
Zheng Chunxiong,
Yi Kaikai,
Zhao Yu,
Gu Yu,
Wang Ying,
Wang Chun,
Zhao Xinzhi,
Shi Linqi,
Kang Chunsheng,
Liu Yang
Publication year - 2019
Publication title -
advanced materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 10.707
H-Index - 527
eISSN - 1521-4095
pISSN - 0935-9648
DOI - 10.1002/adma.201905751
Subject(s) - trans activating crrna , crispr , cancer immunotherapy , internalization , genome editing , tumor microenvironment , cancer research , immunotherapy , materials science , immune system , nanotechnology , biology , microbiology and biotechnology , computational biology , cell , gene , immunology , tumor cells , biochemistry
Abstract The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR‐associated (Cas) enzyme, Cas13a, holds great promise in cancer treatment due to its potential for selective destruction of tumor cells via collateral effects after target recognition. However, these collateral effects do not specifically target tumor cells and may cause safety issues when administered systemically. Herein, a dual‐locking nanoparticle (DLNP) that can restrict CRISPR/Cas13a activation to tumor tissues is described. DLNP has a core–shell structure, in which the CRISPR/Cas13a system (plasmid DNA, pDNA) is encapsulated inside the core with a dual‐responsive polymer layer. This polymer layer endows the DLNP with enhanced stability during blood circulation or in normal tissues and facilitates cellular internalization of the CRISPR/Cas13a system and activation of gene editing upon entry into tumor tissue. After carefully screening and optimizing the CRISPR RNA (crRNA) sequence that targets programmed death‐ligand 1 (PD‐L1), DLNP demonstrates the effective activation of T‐cell‐mediated antitumor immunity and the reshaping of immunosuppressive tumor microenvironment (TME) in B16F10‐bearing mice, resulting in significantly enhanced antitumor effect and improved survival rate. Further development by replacing the specific crRNA of target genes can potentially make DLNP a universal platform for the rapid development of safe and efficient cancer immunotherapies.