Abstract
Small interfering RNA (siRNA) therapeutics hold great promise to treat a variety of diseases, as long as they can be delivered safely and effectively into cells. Dendrimers are appealing vectors for siRNA delivery by virtue of their well-defined molecular architecture and multivalent cooperativity. However, the clinical translation of RNA therapeutics mediated by dendrimer delivery is hampered by the lack of dendrimers that are of high quality to meet good manufacturing practice standard. In this context, we have developed small amphiphilic dendrimers that self-assemble into supramolecular structures, which mimic high-generation dendrimers synthesized with covalent construction, yet are easy to produce in large amount and superior quality. Indeed, the concept of supramolecular dendrimers has proved to be very promising, and has opened up a new avenue for dendrimer-mediated siRNA delivery. A series of self-assembling supramolecular dendrimers have consequently been established, some of them out-performing the currently available nonviral vectors in delivering siRNA to various cell types in vitro and in vivo, including human primary cells and stem cells. This short review presents a brief introduction to RNAi therapeutics, the obstacles to their delivery and the advantages of dendrimer delivery vectors as well as our bio-inspired structurally flexible dendrimers for siRNA delivery. We then highlight our efforts in creating selfassembling amphiphilic dendrimers to construct supramolecular dendrimer nanosystems for effective siRNA delivery as well as the related structural alterations to enhance delivery efficiency. The advent of self-assembling supramolecular dendrimer nanovectors holds great promise and heralds a new era of dendrimer-mediated delivery of RNA therapeutics in biomedical applications.
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Acknowledgements
We acknowledge support from La Ligue Nationale Contre le Cancer (LP), Fondation pour la Recherche Médicale (SPF20150934261, YC), Association pour la Recherche sur les Tumeurs de la Prostate (LP, XL), Association Française contre les Myopathies (XL), the international ERA-Net EURONANOMED European Research projects “DENANORNA”, “Target4Cancer” and “NANOGLIO” (LP), Agence Nationale de la Recherche, CNRS, Aix-Marseille University and China Pharmaceutical University.
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Dr. Ling Peng is currently a research director at the French National Scientific Research Center (CNRS) and a group leader at the Interdisciplinary Center of Nanoscience in Marseille (CINaM), France. She carried out her undergraduate study in polymer science with Prof. Chen Rongshi at Nanjing University in China, her Ph.D. program in organic chemistry with Prof. Albert Eschenmoser at the Swiss Federal Institute of Technology in Zurich, Switzerland, and her postdoctoral research in pharmaceutical science with Prof. Maurice Goeldner at the Louis Pasteur University of Strasbourg in France. She was recruited as a research scientist at CNRS in 1997, and promoted to CNRS research director in 2008. She is working actively at the interface of chemistry and biology, and mainly focused on developing functional dendrimers for drug delivery, and molecular probes for understanding and exploring biological events for drug discovery. In particular, she has pioneered bio-inspired structurally flexible dendrimers for nucleic acid delivery in gene therapy, and inaugurated the concept of self-assembling supramolecular dendrimers for drug delivery. Dr. Ling Peng is currently a member of the Editorial Advisory Board of Molecular Pharmaceutics, section editor of drug delivery for Current Medicinal Chemistry and Assistant Editor of New Journal of Chemistry.
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Cao, Y., Liu, X. & Peng, L. Molecular engineering of dendrimer nanovectors for siRNA delivery and gene silencing. Front. Chem. Sci. Eng. 11, 663–675 (2017). https://doi.org/10.1007/s11705-017-1623-5
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DOI: https://doi.org/10.1007/s11705-017-1623-5