🧬 Excited to share our new work in @NatureBiotech! Paper: nature.com/articles/s41587-0… Research Briefing: nature.com/articles/s41587-0… Large gene editors require large mRNAs, but LNPs are typically discovered using much smaller reporter RNAs. We asked: does RNA size matter when discovering delivery lipids? Using a large base-editor mRNA for high-throughput screening, we identified LC-1, an ionizable lipid that enabled efficient gene editing in the liver, lung, and brain via different administration routes in mice, with up to 4× higher Cas9 editing than benchmark LNPs. LC-1 also efficiently delivered base editors for disease-relevant targets in hypercholesterolemia, cystic fibrosis, and Angelman syndrome. Why does LC-1 work so well? Cryo-EM and X-ray scattering revealed that LC-1 LNPs form an ordered, inverted-hexagonal structure that persists with large RNA cargo. This membrane-fusing structure helps RNA escape from endosomes, the compartments that can trap it inside cells. In cell studies, LC-1 released roughly twice as much large mRNA into the cytosol as the benchmark formulations. We show that LC-1's key design features also apply to ionizable lipids made through other synthetic routes. These findings show that accounting for RNA size from the start can change which lipids we discover and improve delivery of large gene editors. This could help expand the delivery options available for future gene-editing medicines. Thank you to all our co-authors, collaborators and funders @CIHR_IRSC @NSERC_CRSNG @UofTPharmacy @LisaDolovich @PMResearch_UHN @bradwouters #LipidNanoparticles #GeneEditing #RNATherapeutics

A new lipid nanoparticle, LC-1, overcame gene editing barriers and efficiently delivered large RNA tools to the preclinical models of liver, lungs, and brain. The @NatureBiotech study was led by @BowenLi_Lab @UHN @pmcancercentre & @UofTPharmacy: nature.com/articles/s41587-0…

Interpreting transcript diversity requires moving beyond ‘known’ versus ‘novel’ and towards a multidimensional framework based on technical credibility, contextual prevalence, reproducibility, molecular consequence and phenotypic relevance nature.com/articles/s41587-0…

Somatic small variants in cancer genomes are identified in both short-read and long-read data go.nature.com/4qa6m0d rdcu.be/XXFkEQLLSs5a

Deep learning perturbation models can outperform baselines on calibrated metrics - @ShiftBioscience nature.com/articles/s41587-0…

The emerging reproducibility crisis in AI-driven biomedicine will only intensify unless the community redefines multiomics data quality nature.com/articles/s41587-0… rdcu.be/a3yYAYF4vAya

24 hours left to submit your abstract. Don't miss the opportunity to present your work alongside leaders in RNA biology, nucleic acid therapeutics, and clinical translation. go.nature.com/4zcVYIN @NatureBiotech @ionispharma @Alnylam @ucsd_rna_center

Biotech news from around the world: United Kingdom, South Korea, South Africa, Guatemala nature.com/articles/s41587-0… rdcu.be/YoAK6s1KPkba

A scalable blueprint for postdoctoral training embeds entrepreneurial venture mechanics and industry mobility directly into academic infrastructure to cultivate ‘T-shaped’ scientific leaders nature.com/articles/s41587-0… rdcu.be/AaEiyDRp9cSa

Recent moves of note in and around the biotech and pharma industries nature.com/articles/s41587-0… rdcu.be/3p7MDZwAyVxa

Research Highlight: On-demand glycemic control by engineered bacteria nature.com/articles/s41587-0…

DIAL designs synthetic promoters for generation of heritable setpoints of gene expression across a range of cell types go.nature.com/4h9wlR1 rdcu.be/ruJgZuhLT6ra

Scientists uncover thousands of previously missed proteins, many of which appear to be relevant to human health — including promising new targets for cancer immunotherapies nature.com/articles/s41587-0… rdcu.be/kUYzGHZ13eea