Affiliation:
1. Department of Laboratory Medicine Dongguan Institute of Clinical Cancer Research The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital) Dongguan Guangdong 523058 China
2. The Base of Achievement Transformation Shidong Hospital Affiliated to University of Shanghai for Science and Technology Shanghai 200438 China
3. Affiliated Foshan Maternity & Child Healthcare Hospital Southern Medical University (Foshan Maternity & Child Healthcare Hospital) Foshan 528000 China
Abstract
AbstractCRISPR/Cas13a is a powerful genome editing system for RNA knockdown that holds enormous potential for cancer treatment by targeting currently undruggable oncogenes or immune checkpoints. However, the precise intratumoral activation of CRISPR/Cas13a to maximize the therapeutic efficiency while guaranteeing biosafety remains a daunting challenge. Here, a cascade self‐uncloaking nanoassembly (SRC) based on a dual‐prodrug comprising SN38 and Cas13a/RNP is developed, and the external encapsulation is performed by coating with a ROS‐responsive probe, which is stimulated by the tumor microenvironment to achieve the efficient NIR‐II imaging by CH10055 due to disaggregation into single molecules, while the second release of prodrug in the hypoxic environment enables targeted controlled release. SN38 not only induces immunogenic cell death (ICD), but significantly combats the immunosuppressive microenvironment of colorectal cancer in combination with the RNA editing targeting the novel immune checkpoint TIM3 to regulate the cGAS‐STING pathways, resulting in synergistic activation of both innate and adaptive immunity. The treatment of SRC exhibits a tenfold increase in tumor regression of α‐PD‐L1 in PD‐L1‐resistant orthotopic and xenograft models by inducing effective tumor immune infiltration. These results demonstrate the feasibility of using CRISPR/Cas13a in cancer treatment, and SRC holds immense promise as a neoadjuvant strategy for enhancing CRC immunotherapy.
Funder
National Natural Science Foundation of China
China Postdoctoral Science Foundation
Subject
Electrochemistry,Condensed Matter Physics,Biomaterials,Electronic, Optical and Magnetic Materials