Pharmaceutical Biotechnology, Center for System-Based Drug Research, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
Pharmaceutical Biotechnology, Center for System-Based Drug Research, Ludwig-Maximilians-Universität (LMU), Munich, Germany; Center for Nanoscience (CeNS), Ludwig-Maximilians-Universität (LMU), Munich, Germany.
Adv Drug Deliv Rev. 2021 Jan;168:30-54. doi: 10.1016/j.addr.2020.03.005. Epub 2020 Apr 1.
Optimizing synthetic nanocarriers is like searching for a needle in a haystack. How to find the most suitable carrier for intracellular delivery of a specified macromolecular nanoagent for a given disease target location? Here, we review different synthetic 'chemical evolution' strategies that have been pursued. Libraries of nanocarriers have been generated either by unbiased combinatorial chemistry or by variation and novel combination of known functional delivery elements. As in natural evolution, definition of nanocarriers as sequences, as barcode or design principle, may fuel chemical evolution. Screening in appropriate test system may not only provide delivery candidates, but also a refined understanding of cellular delivery including novel, unpredictable mechanisms. Combined with rational design and computational algorithms, candidates can be further optimized in subsequent evolution cycles into nanocarriers with improved safety and efficacy. Optimization of nanocarriers differs for various cargos, as illustrated for plasmid DNA, siRNA, mRNA, proteins, or genome-editing nucleases.
优化合成纳米载体就像是在大海捞针。如何为给定的疾病靶位找到最适合的载体来实现特定的大分子纳米药物的细胞内递送？在这里，我们综述了不同的合成“化学进化”策略。纳米载体库可以通过无偏组合化学或已知功能传递元件的变异和新颖组合来生成。就像在自然进化中一样，将纳米载体定义为序列、条形码或设计原则，可能会激发化学进化。在适当的测试系统中进行筛选不仅可以提供递药候选物，还可以深入了解细胞内递药，包括新的、不可预测的机制。与合理设计和计算算法相结合，候选物可以在后续的进化循环中进一步优化，成为具有更高安全性和疗效的纳米载体。不同的载药需要不同的纳米载体优化，这在质粒 DNA、siRNA、mRNA、蛋白质或基因组编辑核酸酶的例子中得到了说明。
