2. Academic Validation
  3. Layered-Responsive Multivalent Tetrahedral DNA Framework-Decorated CRISPR-Cas12a Nanocapsule Enables Precise and Enhanced Tumor Chemotherapy

Layered-Responsive Multivalent Tetrahedral DNA Framework-Decorated CRISPR-Cas12a Nanocapsule Enables Precise and Enhanced Tumor Chemotherapy

  • ACS Nano. 2025 May 27;19(20):19274-19286. doi: 10.1021/acsnano.5c01747.
Ye Zhang 1,  Wenbin Li 1,  Siting Chen 2 3,  Yu Zhang 2,  Yitong Zhu 2,  Fei Lan 1,  Huijun Du 3,  Rui Fan 1,  Junfang Zhu 4 5,  Weilun Pan 1,  Bo Situ 1,  Lei Zheng 1,  Shihua Luo 4 5,  Xiaohui Yan 1 2
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, Medical Research Center of Nanfang Hospital, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single-cell and Extracellular Vesicles, Nanfang Hospital, Southern Medical University, Guangzhou 510515, P. R. China.
  • 2 School of Basic Medical Sciences, Medical Research Center of Nanfang Hospital, Department of Laboratory Medicine, Southern Medical University, Guangzhou 510515, P. R. China.
  • 3 The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong 511518, P. R. China.
  • 4 Center for Clinical Laboratory Diagnosis and Research, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, P. R. China.
  • 5 Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi of Guangxi Higher Education Institutions, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, P. R. China.
PMID: 40366179 DOI: 10.1021/acsnano.5c01747
Abstract

The lack of selective tumor targeting and the high toxicity of conventional chemotherapy treatments remain major challenges in Cancer therapy. Here, we develop a self-controlled DNA nanostructure-CRISPR-12a system, a triple-locked cascade tumor therapy nanocapsule (Tatna), for efficient and targeted tumor treatment. Tatna integrates structural DNA tetrahedrons (DTs) with high drug-loading capacity, Cas12a/crRNA ribonucleoprotein (Cas12a RNP), and doxorubicin (DOX) to enable multisite response for precise drug delivery and augmented tumor treatment. By incorporation of a nucleolin-targeting aptamer, Tatna achieves selective targeting and efficient tumor cell internalization. Encapsulation in pH-responsive poly l-lactic-co-glycolic acid (PLGA) nanocapsule ensures stable circulation and controlled release of both DOX and Cas12a until tumor-specific activation in the acidic microenvironment. The Cas12a RNP, triggered by APE1 mRNA overexpression in tumor cells, induces trans-cleavage of DTs, releasing DOX and Cas12a to transport into the nucleus and induce enhanced cell Apoptosis. This self-regulating and multifunctional approach enhances the efficacy of chemotherapy while reducing off-target effects. Tatna's programmable, tumor-specific delivery system represents a powerful strategy for advancing precision medicine and personalized Cancer treatment.

Keywords

CRISPR-Cas12a; DNA tetrahedron; chemotherapy; doxorubicin; layered-responsive.

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