Cationic Polymers Enable Internalization of Negatively Charged Chemical Probes into Bacteria.

The bacterial cell envelope provides a protective barrier that is challenging for small molecules and biomolecules to cross. Given the anionic nature of both Gram-positive and Gram-negative bacterial cell envelopes, negatively charged molecules are particularly difficult to deliver into these organisms. Many strategies have been employed to penetrate bacteria, ranging from reagents such as cell-penetrating peptides, enzymes, and metal-chelating compounds to physical perturbations.

Blended Block Polycation Micelles Enhance Antisense Oligonucleotide Delivery.

Nucleic acid-based medicines and vaccines are becoming an important part of our therapeutic toolbox. One key genetic medicine is antisense oligonucleotides (ASOs), which are short single-stranded nucleic acids that downregulate protein production by binding to mRNA. However, ASOs cannot enter the cell without a delivery vehicle.

Enhanced ASO-Mediated Gene Silencing with Lipophilic pH-Responsive Micelles.

Herein, we examine the ASO-mediated gene silencing efficiency of pH-responsive micelles, by incorporating 2-(diisopropylamino)ethyl methacrylate (DIP) into the micelle core and comparing physical and biological properties with non-pH-responsive micelles. Additionally, the lipophilic effect of the micelle cores was examined in both types of micelles. Varying lipophilicity was achieved by varying alkyl monomer chain lengths─butyl (4), lauryl (12), and stearyl (18) methacrylate.

Cationic Micelles Outperform Linear Polymers for Delivery of Antisense Oligonucleotides in Serum: An Exploration of Polymer Architecture, Cationic Moieties, and Cell Addition Order.

Antisense oligonucleotides (ASOs) are an important emerging therapeutic; however, they struggle to enter cells without a delivery vehicle, such as a cationic polymer. To understand the role of polymer architecture for ASO delivery, five linear polymers and five diblock polymers (capable of self-assembly into micelles) were synthesized with varying cationic groups. After complexation of each polymer/micelle with ASO, it was found that less bulky cationic moieties transfected the ASO more effectively.

Polycation Architecture Affects Complexation and Delivery of Short Antisense Oligonucleotides: Micelleplexes Outperform Polyplexes.

Herein, we examine the complexation and biological delivery of a short single-stranded antisense oligonucleotide (ASO) payload with four polymer derivatives that form two architectural variants (polyplexes and micelleplexes): a homopolymer poly(2-dimethylaminoethyl methacrylate) (D), a diblock polymer poly(ethylene glycol)methylether methacrylate--poly(2-dimethylaminoethyl methacrylate) (OD), and two micelle-forming variants, poly(2-dimethylaminoethyl methacrylate)--poly(-butyl methacrylate) (DB) and poly(ethylene glycol)methylether methacrylate--poly(2-dimethylaminoethyl methacrylate)--poly(-butyl methacrylate) (ODB). Both polyplexes and micelleplexes complexed ASOs, and the incorporation of an O brush enhances colloidal stability. Micellplexes are templated by the size and shape of the unloaded micelle and that micelle-ASO complexation is not sensitive to formulation/mixing order, allowing ease, versatility, and reproducibility in packaging short oligonucleotides.