UC Davis

Non-small cell lung cancer (NSCLC) is the largest contributor to cancer mortality in the United States. Traditional chemotherapies are toxic and prone to the development of drug resistance. Recently, several drug candidates were shown to induce lysosomal membrane permeabilization (LMP) in aggressive cancers. This has led to increased interest in lysosome dysregulation as a therapeutic target. However, approaches are needed to overcome two limitations of current lysosomal inhibitors: low specificity and potency. Here, we report the development of a transformable nanomaterial that is triggered to induce LMP of lysosomes in NSCLC. The nanomaterial consists of peptide amphiphiles, which self-assemble into nanoparticles, colocalize with the lysosome, and change conformation to nanofibrils due to lysosomal pH shift, leading to the disruption of the disruption of the lysosome, cell death, and cisplatin sensitization. We have found that this cell-penetrating transformable peptide nanoparticle (CPTNP) was cytotoxic to NSCLC cells in the low-micromolar range, synergizing cisplatin cytotoxicity four-fold. Moreover, we demonstrate CPTNP's promising antitumor effect in mouse xenograft models with limited toxicity when given in combination with low-dose cisplatin chemotherapy. CPTNPs the first example of enhanced LMP via transformable peptide nanomaterial and offers a promising new strategy for cancer therapy. Crispr-Cas genome editing promises to revolutionize medicine as it is currently conceived; if it can overcome the challenge of target tissue delivery. Several CRISPR-Cas delivery systems have been developed which can systemically edit somatic tissue in vivo if IV delivered. However, no system currently exists which can edit somatic cells after the oral delivery of CRISPR-Cas. Hepatitis E virus like nanoparticles, were originally developed by the Cheng group and have previously been used to deliver plasmid-based vaccines orally, and are a promising platform for the oral delivery of nucleic acid and protein cargos. Herein we develop Cas9 ribonucleoprotein -loaded Hepatitis E virus-like nanoparticles capable of delivering CRISPR-Cas editing systems in vivo via the oral route. We demonstrate 39% editing efficiency in vitro and up to 10% editing efficiency in the crypts of small intestinal tissue. This is the first example of orally available Crispr-Cas gene editing. Together these systems represent two novel nano-systems which make major advancements in self-assembling cancer therapeutics and orally available gene editing.