The oral delivery of bioactive peptides and proteins is prevented by the intestinal epithelial barrier, in which intercellular tight junction complexes block the uptake of macromolecules. Here, we show that anionic nanoparticles induce tight junction relaxation, increasing intestinal permeability and enabling the oral delivery of proteins. This permeation-enhancing effect is a function of nanoparticle size and charge, with smaller (≤ 200 nm) and more negative particles (such as silica) conferring enhanced permeability. In healthy mice, silica nanoparticles enabled the oral delivery of insulin and exenatide, with a 10 U/kg of orally delivered insulin sustaining hypoglycaemia for a few hours longer than a 1 U/kg dose of subcutaneously injected insulin. In healthy, hyperglycaemic and diabetic mice, the oral delivery of 10 U/kg of insulin led to a dose-adjusted bioactivity of, respectively, 35%, 29%, and 23% compared to 1 U/kg subcutaneously injected insulin. The permeation-enhancing effect of the nanoparticles was reversible, non-toxic, and attributable to the binding to integrins on the surface of epithelial cells.Oral drug delivery, which is painless and convenient, offers superior patient compliance and improved disease outcomes compared to injections. However, delivery challenges have thwarted its successful implementation for decades. Every day, millions of patients across the globe are subjected to injections of macromolecular drugs, such as insulin or heparin. Unfortunately, a fear of injections is pervasive across populations, sometimes surpassing 80% prevalence in both children and adults 1,2 . An estimated 20%−30% of patients further classify as suffering from severe needle phobia 2,3 . As a result, up to 33% of diabetic patients report feelings of dread associated with their insulin injections, and 45%−60% report intentionally skipping one or more doses 4,5 . By enabling painless self-administration, oral Reprints and permissions information is available at www.nature.com/reprints.

The clinical translation of messengerRNA (mRNA) drugs has been slowed by a shortage of delivery vehicles that potently and safely shuttle mRNA into target cells. Here, we describe the properties of a particularly potent branched-tail lipid nanoparticle that delivers mRNA to >80% of

To accelerate the translation of cancer nanomedicine, we used an integrated genomic approach to improve our understanding of the cellular processes that govern nanoparticle trafficking. We developed a massively parallel screen that leverages barcoded, pooled cancer cell lines annotated with multiomic data to investigate cell association patterns across a nanoparticle library spanning a range of formulations with clinical potential. We identified both materials properties and cell-intrinsic features that mediate nanoparticle-cell association. Using machine learning algorithms, we constructed genomic nanoparticle trafficking networks and identified nanoparticle-specific biomarkers. We validated one such biomarker: gene expression of SLC46A3 , which inversely predicts lipid-based nanoparticle uptake in vitro and in vivo. Our work establishes the power of integrated screens for nanoparticle delivery and enables the identification and utilization of biomarkers to rationally design nanoformulations.

Several potent derivatives, including 1-methyl-4-phenylpiperazine and 1-(4-methylphenyl)piperazine, displayed lower toxicity than 1-phenylpiperazine, suggesting promise in future applications.

Background Inflammatory bowel disease (IBD) is a family of debilitating disorders that affects more than 1 million people in the United States. Many animal studies of IBD use a dextran sulfate sodium (DSS) mouse model of colitis that induces rapid and severe colitis symptoms. Although the typical seven-day DSS model is appropriate for many studies, it destroys intestinal barrier function and results in intestinal permeability that is substantially higher than what is typically observed in patients. As such, therapies that enhance or restore barrier integrity are difficult or impossible to evaluate. Methods We identify administration conditions that result in more physiologically relevant intestinal damage by systematically varying the duration of DSS administration. We administered 3.0% DSS for four to seven days and assessed disease metrics including weight, fecal consistency, intestinal permeability, spleen weight, and colon length. Histology was performed to assess the structural integrity of the intestinal epithelium. Results Extended exposure (seven days) to DSS resulted in substantial, unrecoverable loss of intestinal structure and intestinal permeability increases of greater than 600-fold. Attenuated DSS administration durations (four days) produced less severe symptoms by all metrics. Intestinal permeability increased only 8-fold compared to healthy mice, better recapitulating the 2–18 fold increases in permeability observed in patients. The attenuated model retains the hallmark properties of colitis against which to compare therapeutic candidates. Our results demonstrate that an attenuated DSS colitis model obtains clinically relevant increases in intestinal permeability, enabling the effective evaluation of therapeutic candidates that promote barrier function.