Abstract There is no doubt regarding the therapeutic potential of nucleic acids (NA). However, to be functional NA require delivery into the cytoplasm or nucleus of the target cell. To overcome the extra-and intracellular barriers, NA are generally packaged into nanoparticles (i.e. nanomedicines). Unfortunately, current nanomedicines largely fail to deliver their NA cargo to its intracellular site of action. Interestingly, increasing evidence exists that major delivery hurdles can in part be overcome through helpful biological functions of low molecular weight compounds. This review summarizes how various (classes of) compounds can intervene at distinct stages of the NA delivery pathway. Small molecules are reported to influence processes including nanomedicine internalization, endosomal escape, intracellular trafficking and transgene expression. Of note, a number of compounds exert their effect by simultaneously affecting several of these steps. Interestingly, the low molecular weight adjuvants can be incorporated into the nanocarrier, conjugated to the nucleic acid or added before, during or after nanocarrier administration, indicating the versatility of this approach.

中文翻译：

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小分子传递大信息：用低分子量药物促进非病毒核酸递送

摘要 核酸 (NA) 的治疗潜力是毋庸置疑的。然而，要发挥功能性 NA 需要递送到靶细胞的细胞质或细胞核中。为了克服细胞外和细胞内的障碍，NA通常被包装成纳米颗粒（即纳米药物）。不幸的是，目前的纳米药物在很大程度上无法将其 NA 货物输送到其细胞内作用位点。有趣的是，越来越多的证据表明，通过低分子量化合物的有益生物功能，可以部分克服主要的传递障碍。本综述总结了各种（类别）化合物如何干预 NA 递送途径的不同阶段。据报道，小分子会影响包括纳米药物内化、内体逃逸、细胞内运输和转基因表达在内的过程。值得注意的是，许多化合物通过同时影响这些步骤中的几个来发挥其作用。有趣的是，低分子量佐剂可以掺入纳米载体中，与核酸结合或在纳米载体给药之前、期间或之后添加，表明这种方法的多功能性。