A novel anti-microRNA delivery platform that targets the acidic tumour microenvironment, in which a chosen anti-miRNA is coupled to a peptide that can transport the anti-miRNA across cell membranes specifically in an acidic environment. The targeted silencing of certain aberrantly expressed microRNAs (miRNAs) — known as oncomiRs — may prove useful for cancer therapy if the silencing agents can be efficiently delivered to the tumours. Frank Slack and colleagues now exploit the generally acidic tumour environment by devising nanoparticle-based delivery vehicles in which a chosen anti-miR is coupled to a peptide that can transport the anti-miR across cell membranes specifically in an acidic environment. In a lymphoma mouse model, this formulation can specifically target anti-miR-155 to those tumours whose growth depends on miR-155 expression, reducing tumour growth and metastases without apparent toxicity to the mice. This approach should be widely applicable for targeting a variety of tumours with an anti-miR of choice. MicroRNAs are short non-coding RNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, microRNAs are critical cogs in numerous biological processes1,2, and dysregulated microRNA expression is correlated with many human diseases. Certain microRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed. Tumours that depend on these microRNAs are said to display oncomiR addiction3,4,5. Some of the most effective anticancer therapies target oncogenes such as EGFR and HER2; similarly, inhibition of oncomiRs using antisense oligomers (that is, antimiRs) is an evolving therapeutic strategy6,7. However, the in vivo efficacy of current antimiR technologies is hindered by physiological and cellular barriers to delivery into targeted cells8. Here we introduce a novel antimiR delivery platform that targets the acidic tumour microenvironment, evades systemic clearance by the liver, and facilitates cell entry via a non-endocytic pathway. We find that the attachment of peptide nucleic acid antimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP) produces a novel construct that could target the tumour microenvironment, transport antimiRs across plasma membranes under acidic conditions such as those found in solid tumours (pH approximately 6), and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma. This study introduces a new model for using antimiRs as anti-cancer drugs, which can have broad impacts on the field of targeted drug delivery.

MicroRNA silencing for cancer therapy targeted to the tumour microenvironment