A Combinatorial Library of Biodegradable Lipid Nanoparticles Preferentially Deliver mRNA into Tumor Cells to Block Mutant RAS Signaling

Abstract

Messenger RNA (mRNA) is an emerging class of biotherapeutics for vaccine development and genome editing. Efficacious delivery and control of mRNA functionality selectively to disease cells remains the major challenge in developing mRNA therapeutics. Herein, reactive oxygen species (ROS)degradable lipid nanoparticles containing a thioketal (TK) moiety to deliver mRNA into cells are reported, selectively releasing mRNA in tumor cells for enhanced gene expression. By screening a library of parallelly synthesized ROS-degradable lipids, it has been identified that BAmP-TK-12 delivers mRNA one-fold more potent in tumor cells than in non-cancerous cells. Furthermore, the delivery of mRNA encoding DUF5, a bacterial-derived RAS protease using BAmP-TK-12 enables generic depletion of mutant RAS of tumor cells, showing a significantly improved antitumor effect than small molecule-based RAS inhibitor. It has been believed that the strategy of tumor cell-selective mRNA delivery using ROS-degradable lipid nanoparticles can be expanded to the broad range of bacterial effectors for rewiring cancer cell signaling and developing advanced biotherapeutics.

Self-Assembling NIR-Responsive Recombinant Protein Complex Nanoparticles for Synergistic Treatment of Malignant Tumors

“…The measured diameter of KPP was mainly distributed in the range of 40–80 nm, thus conferring accumulation into tumor sites via the enhanced permeability and retention effect. Furthermore, KPP exhibited a drug loading efficiency of 28.7% and encapsulation efficiency of 36.9%, which are high enough in comparison with liposomes and polymeric micelles. , Subsequently, the assembly and adhesion of PDA were intervened on nanoscale interfaces by spontaneous oxidation and self-polymerization to obtain the photothermal and neuromodulated effect . The KPPD nanoparticles were finally fabricated by the supramolecular self-assembly of electrostatic and hydrophobic interactions and π–cation interactions .…”

Orthogonal Chemical Activation of Enzyme-Inducible CRISPR/Cas9 for Cell-Selective Genome Editing

“…To overcome these limitations, we formulated eiCRISPR containing 17E-BA or 17E-QP DNAzyme with a new type of LNPs, BAmP-TK-12 that are biodegradable to preferably deliver mRNA into cancer cells (Figure S9a,b). , BAmP-TK-12-mediated delivery of eiCRISPR enabled the controlled release of eiCRISPR inside tumor cells by making use of the upregulated cellular ROS that degraded BAmP-TK-12, facilitating the selective activation of eiCRISPR by tumoral NQO1. The formulated BAmP-TK-12/eiCRISPR nanoparticles were around 100 nm in diameter and positively charged, as measured by dynamic light scattering analysis (Figure S9c,d).…”

High‐Precision Synthesis of RNA‐Loaded Lipid Nanoparticles for Biomedical Applications

“…[ 114 ] Nevertheless, the inverted hexagonal phase (H II ) structures ( P c > 1) is the most actively studied phase for RNA transfection using LNP as the conical‐shape morphology facilitates the destabilization of endosomal membrane followed by nucleic acid delivery into the cytosol and subsequent protein expression in vivo. [ 5,97,102,103,114,115 ]…”

“…Reproduced with permissions. [ 97 ] Copyright 2022, Wiley‐VCH GmbH. c) Schematic illustration of siRNA‐loaded tLNP as well as tumor volume change chart according to administration date.…”