Cargo-selective and adaptive delivery of nucleic acid therapeutics by bola-amphiphilic dendrimers
Jiaxuan Chen, Dandan Zhu, Baoping Lian, Kangjie Shi, Peng Chen, Ying Li, Wenyi Lin, Ling Ding, Qiulin Long, Yang Wang, Erik Laurini, Wenjun Lan, Yun Li, Aura Tintaru, Caoyun Ju, Can Zhang, Sabrina Pric, Juan Iovanna, Xiaoxuan Liu, Ling Peng
May 15, 2023, 120 (21) e2220787120
DOI: www.pnas.org/doi/10.1073/pnas.2220787120
Tailor-made functional materials that meet specific requirements for different applications are of great importance in material and biomedical research. Dendrimers, by virtue of their well-defined structure and cooperative multivalence, represent precision materials. Recently, we synthesized and studied bipolar (bola) amphiphilic dendrimers for selective and on-demand delivery of DNA and small interfering RNA (siRNA), both are important nucleic acid therapeutics (Figure). Nucleic acid therapeutics are becoming a new drug modality, offering the unique opportunity to target “undruggable” targets, respond rapidly to evolving pathogens, and treat diseases at the genetic level for precision medicine. However, nucleic acid therapeutics suffer from poor bioavailability and are susceptible to chemical and enzymatic degradation, necessitating the use of delivery vectors.
By employing bola-amphiphilic dendrimers, we achieved superior performance in siRNA delivery with the second-generation dendrimer, whereas the third-generation dendrimer showed excellent DNA delivery. We systematically investigated these dendrimers in terms of cargo binding, cellular uptake, endosomal release, and in vivo delivery. The differences in size between the dendrimers and their nucleic acid cargos affected the cooperative multivalent interactions for cargo/vector binding and release, resulting in adaptive and selective cargo delivery. Furthermore, both dendrimers capitalized on the advantages of lipid and polymer vectors, while also providing tumor-targeting capabilities based on nanotechnology and redox-responsive cargo release. Notably, they enabled tumor- and cancer cell-specific delivery of siRNA and DNA therapeutics, leading to effective treatment in various cancer models, including aggressive and metastatic malignancies. These dendrimers outperformed currently available vectors. This study will inspire further exploitation of tailor-made dendrimer platforms for the cargo-selective delivery of various therapeutics in precision medicine.
This collaborative study involved the Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), China Pharmaceutical University, Trieste University and the Centre de Recherche en Cancérologie de Marseille (CRCM).
Bola-amphiphilic dendrimers for cargo-specific nucleic acid delivery. (A) Chemical structures of the bola-amphiphilic dendrimers bola2A, bola4A, and bola8A studied in this work. (B) Cartoon illustration of bola-amphiphilic dendrimers bola4A and bola8A for cargo-selective and adaptive delivery of the two distinct nucleic acid types, DNA and siRNA.