Spatiotemporally delivery of Cas9 ribonucleoprotein/DNAzyme logic systems using near-infrared upconversion nanomachine for precise immunotherapy.
10.1016/j.apsb.2025.07.010
- Author:
Chao CHEN
1
;
Shiyu DU
2
;
Qianglan LU
2
;
Xueting SHEN
1
;
Shuai DING
1
;
Lihua QU
3
;
Yamei GAO
4
;
Zhiqiang YIN
4
;
Zhe LI
2
;
Yujun SONG
2
;
Xin HAN
1
Author Information
1. The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
2. College of Engineering and Applied Sciences, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing 210023, China.
3. School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Hubei 437000, China.
4. Department of Dermatology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
- Publication Type:Journal Article
- Keywords:
Cancer immunotherapy;
Cas9 ribonucleoprotein;
Gene therapy;
LncRNA;
PC linker;
Self-assembly DNAzyme;
Upconversion nanoparticles;
cGAS–STING signaling
- From:
Acta Pharmaceutica Sinica B
2025;15(10):5431-5443
- CountryChina
- Language:English
-
Abstract:
Gene therapy, harnessing the power of CRISPR-Cas9 and/or DNAzyme systems, stands as a pivotal approach in cancer therapy, enabling the meticulous manipulation of genes pivotal to tumorigenesis and immunity. However, the pursuit of precise gene therapy encounters formidable hurdles. Herein, a near-infrared upconversion theranostic nanomachine is devised and tailors for CRISPR-Cas9/DNAzyme systems mediate precise gene therapy. An ingenious logic DNAzyme system consists of Chain 1 (C1)/Chain 2 (C2) and endogenous lncRNA is designed. We employ manganese modified upconversion nanoparticles for carrying ultraviolet-responsive C1-PC linker-C2 (C2P) chain and Cas9 ribonucleoprotein (RNP), with outermost coats with hyaluronic acid. Upon reaching tumor microenvironment (TME), the released Mn2+ ions orchestrate a trifecta: facilitating endosomal escape, activating cGAS-STING signaling, and enabling T1-magnetic resonance imaging. Under near-infrared irradiation, Cas9 RNP/C2P complex dissociates, releasing Cas9 RNP into the nucleus to perform gene editing of Ptpn2, while C1/C2 chains self-assemble with endogenous lncRNA to form a functional DNAzyme system, targeting PD-L1 mRNA for gene silencing. This strategy remodels the TME by activating cGAS-STING signaling and dual immune checkpoints blockade, thus realizing tumor elimination. Our theranostic nanomachine armed with the CRISPR-Cas9/DNAzyme logic systems, represents a resourceful and promising strategy for advancing cancer systemic immunotherapy and precise gene therapy.
