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Abstract RNA modifications play a pivotal role in the regulation of RNA chemistry within cells. Several technologies have been developed with the goal of using RNA modifications to regulate cellular biochemistry selectively, but achieving selective and precise modifications remains a challenge. Here, we show that by using designer organelles, we can modify mRNA with pseudouridine in a highly selective and guide-RNA-dependent manner. We use designer organelles inspired by concepts of phase separation, a central tenet in developing artificial membraneless organelles in living mammalian cells. In addition, we use circular guide RNAs to markedly enhance the effectiveness of targeted pseudouridinylation. Our studies introduce spatial engineering through optimized RNA editing organelles (OREO) as a complementary tool for targeted RNA modification, providing new avenues to enhance RNA modification specificity.

The acidic tumour microenvironment in melanoma drives immune evasion by cAMP in tumor-infiltrating monocytes. Here, the authors show that the release of an adenylate cyclase inhibitor from micelles restores antitumor immunity and, when combined with regulatory T cell depletion, leads to remission of established B16-F10-OVA tumors.

The E3 ligase Hakai can interact with the m6A methylation machinery but its function is still unclear. Here, the authors show that Hakai is a conserved component of the m6A methyltransferase complex and provide functional and molecular insights into its role in regulating m6A levels in Drosophila.

A controversial discussion on the occurrence of the RNA modification m1A in mRNA takes a new turn, as an antibody with a central role in modification mapping was shown to also bind mRNA cap structures.

Trypanosoma brucei mainly relies on translational regulation to adjust gene expression, but details are unclear. Here the authors show that, under stress conditions, tRNAThr half level increases, associates with ribosomes and polysomes, and stimulates protein synthesis by facilitating mRNA loading.

While nanocarrier-based drug delivery is a promising therapeutic approach, in situ characterization of drug nanocarriers in blood remains difficult. Here, the authors demonstrate how the fluorescence correlation spectroscopy can be used to directly characterize drug nanocarriers in flowing blood.