Nucleic acids are a rapidly emerging therapeutic modality with the potential to become the third major drug modality alongside antibodies and small molecules. Owing to the unfavourable physico-chemical characteristics of nucleic acids, such as large size and negative charge, intracellular delivery remains a fundamental challenge to realizing this potential. Delivery technologies such as lipids, polymers and peptides have been used to facilitate delivery, with many of the most successful technologies using macropinocytosis to gain cellular entry; mostly by default rather than design. Fundamental knowledge of macropinocytosis is rapidly growing, presenting opportunities to better tailor design strategies to target this pathway. Furthermore, certain types of tumour cells have been observed to have high levels of macropinocytic activity and traffic cargo to favourable destinations within the cell for endosomal release, providing unique opportunities to further use this entry route for drug delivery. In this article, we review the delivery systems reported to be taken up by macropinocytosis and what is known about the mechanisms for regulating macropinocytosis in tumour cells. From this analysis, we identify new opportunities for exploiting this pathway for the intracellular delivery of nucleic acids to tumour cells. This article is part of the Theo Murphy meeting issue 'Macropinocytosis'.
Keywords: intracellular drug delivery; macropinocytosis; nanoparticle; nucleic acids; oncology.