Cargo-selective and adaptive delivery of nucleic acid therapeutics by bola-amphiphilic dendrimers

被引：21

作者：

Chen, Jiaxuan ^{[1
,2
]}

Zhu, Dandan ^{[1
]}

Lian, Baoping ^{[1
]}

Shi, Kangjie ^{[1
]}

Chen, Peng ^{[1
,2
]}

Li, Ying ^{[1
]}

Lin, Wenyi ^{[1
]}

Ding, Ling ^{[2
]}

Long, Qiulin ^{[1
]}

Wang, Yang ^{[2
,3
]}

Laurini, Erik ^{[4
]}

Lan, Wenjun ^{[2
,5
]}

Li, Yun ^{[1
]}

Tintaru, Aura ^{[2
]}

Ju, Caoyun ^{[1
]}

Zhang, Can ^{[1
]}

Pricl, Sabrina ^{[4
,6
]}

Iovanna, Juan ^{[5
]}

Liu, Xiaoxuan ^{[1
]}

Peng, Ling ^{[2
]}

机构：

[1] China Pharmaceut Univ, Ctr Adv Pharmaceut & Biomat, Ctr Drug Discovery, State Key Lab Nat Med,Jiangsu Key Lab Drug Discove, Nanjing 211198, Peoples R China

[2] Aix Marseille Univ, CNRS, Ctr Interdisciplinaire Nanosci Marseille, Equipe Labellisee Ligue Canc,UMR 7325, F-13288 Marseille, France

[3] Hubei Gedian Humanwell Pharmaceut Co Ltd, Ezhou 436070, Peoples R China

[4] Univ Trieste, Dept Engn & Architecture, Mol Biol & Nanotechnol Lab, I-34127 Trieste, Italy

[5] Aix Marseille Univ, INSERM, Ctr Rech Cancerol Marseille, Inst Pauli Calmettes, F-13273 Marseille, France

[6] Univ Lodz, Fac Biol & Environm Protect, Dept Gen Biophys, PL-90136 Lodz, Poland

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2023年 / 120卷 / 21期

基金：

中国国家自然科学基金;

关键词：

dendrimer; nucleic acid delivery; nonviral vectors; silencing; gene transfection; LIPID NANOPARTICLES; SIRNA DELIVERY; IN-VIVO; GENE; RNA; BOLAAMPHIPHILES; DESIGN;

D O I：

10.1073/pnas.2220787120

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Nucleic acid therapeutics are becoming an important drug modality, offering the unique opportunity to address "undruggable" targets, respond rapidly to evolving pathogens, and treat diseases at the gene level for precision medicine. However, nucleic acid ther-apeutics have poor bioavailability and are chemolabile and enzymolabile, imposing the need for delivery vectors. Dendrimers, by virtue of their well-defined structure and coop-erative multivalence, represent precision delivery systems. We synthesized and studied bola-amphiphilic dendrimers for cargo-selective and on-demand delivery of DNA and small interfering RNA (siRNA), both important nucleic acid therapeutics. Remarkably, superior performances were achieved for siRNA delivery with the second-generation dendrimer, yet for DNA delivery with the third generation. We systematically studied these dendrimers with regard to cargo binding, cellular uptake, endosomal release, and in vivo delivery. Differences in size both of the dendrimers and their nucleic acid cargos impacted the cooperative multivalent interactions for cargo binding and release, lead-ing to cargo-adaptive and selective delivery. Moreover, both dendrimers harnessed the advantages of lipid and polymer vectors, while offering nanotechnology-based tumor targeting and redox-responsive cargo release. Notably, they allowed tumor-and cancer cell-specific delivery of siRNA and DNA therapeutics for effective treatment in different cancer models, including aggressive and metastatic malignancies, outperforming the currently available vectors. This study provides avenues to engineer tailor-made vectors for nucleic acid delivery and precision medicine.

引用

页数：11

共 52 条

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