Multistage Delivery Nanoparticle Facilitates Efficient
CRISPR/dCas9 Activation and Tumor Growth Suppression In Vivo
Liu, Q (Liu, Qi)[ 1 ] ; Zhao, K (Zhao, Kai)[ 2 ] ; Wang, C (Wang, Chun)[ 1 ] ; Zhang, ZZ (Zhang,
Zhanzhan)[ 1 ] ; Zheng, CX (Zheng,
Chunxiong)[ 1 ] ; Zhao, Y(Zhao, Yu)[ 1 ] ; Zheng, YD (Zheng, Yadan)[ 1 ] ; Liu, CY (Liu,
Chaoyong)[ 2 ] ; An, YL (An, Yingli)[ 1 ] ; Shi, LQ (Shi, Linqi)[ 1 ] ; Kang, CS (Kang,
Chunsheng)[ 2 ] ; Liu, Y(Liu,
Yang)[ 1 ]
ADVANCED SCIENCE, 2019, 6(1): 文献号: 1801423
DOI: 10.1002/advs.201801423
Abstract
CRISPR/dCas9
systems can precisely control endogenous gene expression without interrupting
host genomic sequence and have provided a novel and feasible strategy for the
treatment of cancers at the transcriptional level. How- ever, development of
CRISPR/dCas9-based anti-cancer therapeutics remains challenging due to the
conflicting requirements for the design of the delivery system: a cationic and
membrane-binding surface facilitates the tumor accumulation and cellular uptake
of the CRISPR/dCas9 system, but hinders the circulating stability in vivo.
Here, a multistage delivery nanoparticle (MDNP) that can achieve tumor-targeted
delivery of CRISPR/dCas9 systems and restore endogenous microRNA (miRNA)
expression in vivo is described. MDNP is designed as a core-shell structure in
which the shell is made of a responsive polymer that endows MDNP with the
capability to present different surface properties in response to its
surrounding microenvironment, allowing the MN DP overcoming multiple
physiological barriers and delivering the payload to tumor tissues with an
optimal efficiency. Systemic administration of MDNP/dCas9-miR-524 to
tumor-bearing mice achieved effective upregulation of miR-524 in tumors,
leading to the simultaneous interferences of multiple signal pathways related
to cancer cell proliferation and presenting remarkable tumor growth
retardation, suggesting the feasibility of utilizing MDNP to achieve
tumor-targeting delivery of CRISPR/dCas9 with sufficient levels to realize its
therapeutic effects.
