Nat. Commun. 10, 1894 (2019)

Non-viral RNA delivery for gene therapy is often achieved by encapsulating nucleic acid cargoes within nanoparticles. When applied to oncotherapy, however, these nanoparticles can be too big to penetrate the dense tumour microenvironment that characterizes certain tumours and are cleared in the spleen and liver, reducing the efficacy of the treatments.

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Springer Nature Ltd

Watanabe and colleagues design a small Y-shaped molecule consisting of a positively charged polylysine stretch and two polyethylene glycol (PEG) arms. When injected in specific proportions in the bloodstream of mouse models, the molecule associates in a dynamic equilibrium with desired single- or double-stranded RNAs. Tweaking the number of positive charges and the length of the PEG arms allows stabilization of the RNAs via ionic interactions, and modulation of the lifetimes of the complexes that form. Using these chaperones, the authors efficiently deliver therapeutic RNAs to a pancreatic cancer and glioma, showing deep penetration of the RNAs in the tumours and limited accumulation in the spleen and liver. These cancers have so far been challenging to target due to the thickness of the tumour microenvironment and the presence of a tight blood–brain tumour barrier that filters out large nanoparticles.