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Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2023

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

Jiaxuan Chen
Dandan Zhu
  • Fonction : Auteur
Baoping Lian
  • Fonction : Auteur
Kangjie Shi
  • Fonction : Auteur
Peng Chen
  • Fonction : Auteur
Ying Li
  • Fonction : Auteur
Wenyi Lin
  • Fonction : Auteur
Ling Ding
Qiulin Long
  • Fonction : Auteur
Yang Wang
  • Fonction : Auteur
Erik Laurini
Wenjun Lan
  • Fonction : Auteur
Yun Li
  • Fonction : Auteur
Aura Tintaru
Caoyun Ju
  • Fonction : Auteur
Can Zhang
Sabrina Pricl
Xiaoxuan Liu
  • Fonction : Auteur
  • PersonId : 1081901

Résumé

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 therapeutics have poor bioavailability and are chemolabile and enzymolabile, imposing the need for delivery vectors. Dendrimers, by virtue of their well-defined structure and cooperative 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, leading 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.
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Origine : Publication financée par une institution

Dates et versions

hal-04099741 , version 1 (17-05-2023)

Identifiants

Citer

Jiaxuan Chen, Dandan Zhu, Baoping Lian, Kangjie Shi, Peng Chen, et al.. Cargo-selective and adaptive delivery of nucleic acid therapeutics by bola-amphiphilic dendrimers. Proceedings of the National Academy of Sciences of the United States of America, 2023, 120 (21), pp.e2220787120. ⟨10.1073/pnas.2220787120⟩. ⟨hal-04099741⟩
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