Wesselhoeft, R. A. | Search bioRxiv

bioRxiv2026

Mechanically-mediated low-pressure cell membrane poration enables tunable intracellular delivery of traditionally impermeable cargoes in high throughput and clinical scale formats

Traditional intracellular delivery methods suffer from cargo inefficiencies, non-linear delivery kinetics, and cellular trauma. We designed a mechanically-mediated poration platform governed by deterministic, passive diffusion operating at low pressure which enables dose-dependent, cargo-agnostic intracellular delivery and preserves cellular homeostasis; key advantages include high-fidelity multiplexing, transient cell engineering, and direct-to-biology live-cell target engagement enabling development of novel intracellular delivery applications across drug discovery and cell therapy. We demonstrate examples including live-cell DEL discovery and MOA studies, complex and rapid cell therapy manufacturing, and assay development in sensitive primary cell types.

cell biology↗

bioRxiv2026

An RNA Language Model trained on sequence alone reveals the structural logic of Internal Ribosome Entry Sites

Millions of RNA sequences are readily available, but the structures that determine their function are not. Picornaviruses initiate translation through Internal Ribosome Entry Sites (IRESes), RNA elements that recruit ribosomes independent of the 5` cap. These elements are large and highly divergent, and structural understanding remains limited to a handful of cases. We address this bottleneck by introducing an RNA language model (Albatross), trained purely on sequence, that predicts high-quality IRES structures at scale. We collect in cellulo chemical probing data for 96 full-length IRESes from divergent viruses and show that Albatross achieves far higher precision (0.80) than state-of-the-art predictions (0.47). Analyzing 75,000 IRES structures, we discover a novel Type II structural subclass and validate it experimentally. We demonstrate the pipeline broadly generalizes to identify functional structures, including tertiary contacts and alternative riboswitch structures. These findings establish Albatross as a scalable framework that accelerates RNA structure discovery and antiviral targeting.

molecular biology↗