Precise Photoremovable Perturbation of a Virus–Host Interaction

Viruses utilize distinct binding interactions with a variety of host factors to gain entry into host cells. A chemical strategy is described to precisely perturb a specific molecular interaction between adeno‐associated virus and its host cell, which can be rapidly reversed by light. This strategy enables pausing the virus entry process at a specific stage and then restart it rapidly with a non‐invasive stimulus. The ability to synchronize the invading virus population at a discrete step in its entry pathway will be highly valuable for enabling facile experimental characterization of the molecular processes underlying this process. Additionally, adeno‐associated virus has demonstrated outstanding potential for human gene therapy. This work further provides a potential approach to create therapeutic vectors that can be photoactivated in vivo with high spatial and temporal control.     

Remote Loading of Small‐Molecule Therapeutics into Cholesterol‐Enriched Cell‐Membrane‐Derived Vesicles

The increasing popularity of biomimetic design principles in nanomedicine has led to therapeutic platforms with enhanced performance and biocompatibility. This includes the use of naturally derived cell membranes, which can bestow nanocarriers with cell‐specific functionalities. Herein, we report on a strategy enabling efficient encapsulation of drugs via remote loading into membrane vesicles derived from red blood cells. This is accomplished by supplementing the membrane with additional cholesterol, stabilizing the nanostructure and facilitating the retention of a pH gradient. We demonstrate the loading of two model drugs: the chemotherapeutic doxorubicin and the antibiotic vancomycin. The therapeutic implications of these natural, remote‐loaded nanoformulations are studied both in vitro and in vivo using animal disease models. Ultimately, this approach could be used to design new biomimetic nanoformulations with higher efficacy and improved safety profiles.     

Modular Assembly of Reversible Multivalent Cancer‐Cell‐Targeting Drug Conjugates

Herein is described a new modular platform for the construction of cancer‐cell‐targeting drug conjugates. Tripodal boronate complexes featuring reversible covalent bonds were designed to accommodate a cytotoxic drug (bortezomib), poly(ethylene glycol) (Peg) chains, and folate targeting units. The B‐complex core was assembled in one step, proved stable under biocompatible conditions, namely, in human plasma (half‐life up to 60 h), and underwent disassembly in the presence of glutathione (GSH). Stimulus‐responsive intracellular cargo delivery was confirmed by confocal fluorescence microscopy, and a mechanism for GSH‐induced B‐complex hydrolysis was proposed on the basis of mass spectrometry and DFT calculations. This platform enabled the modular construction of multivalent conjugates with high selectivity for folate‐positive MDA‐MB‐231 cancer cells and IC₅₀ values in the nanomolar range.     

A Double‐Imprinted Diffraction‐Grating Sensor Based on a Virus‐Responsive Super‐Aptamer Hydrogel Derived from an Impure Extract

The detection of viruses is of interest for a number of fields including biomedicine, environmental science, and biosecurity. Of particular interest are methods that do not require expensive equipment or trained personnel, especially if the results can be read by the naked eye. A new “double imprinting” method was developed whereby a virus‐bioimprinted hydrogel is further micromolded into a diffraction grating sensor by using imprint‐lithography techniques to give a “Molecularly Imprinted Polymer Gel Laser Diffraction Sensor” (MIP‐GLaDiS). A simple laser transmission apparatus was used to measure diffraction, and the system can read by the naked eye to detect the Apple Stem Pitting Virus (ASPV) at concentrations as low as 10 ng mL⁻¹, thus setting the limit of detection of these hydrogels as low as other antigen‐binding methods such as ELISA or fluorescence‐tag systems.     

Glyceride‐Mimetic Prodrugs Incorporating Self‐Immolative Spacers Promote Lymphatic Transport,Avoid First‐Pass Metabolism,and Enhance Oral Bioavailability

First‐pass hepatic metabolism can significantly limit oral drug bioavailability. Drug transport from the intestine through the lymphatic system, rather than the portal vein, circumvents first‐pass metabolism. However, the majority of drugs do not have the requisite physicochemical properties to facilitate lymphatic access. Herein, we describe a prodrug strategy that promotes selective transport through the intestinal lymph vessels and subsequent release of drug in the systemic circulation, thereby enhancing oral bioavailability. Using testosterone (TST) as a model high first‐pass drug, glyceride‐mimetic prodrugs incorporating self‐immolative (SI) spacers, resulted in remarkable increases (up to 90‐fold) in TST plasma exposure when compared to the current commercial product testosterone undecanoate (TU). This approach opens new opportunities for the effective development of drugs where oral delivery is limited by first‐pass metabolism and provides a new avenue to enhance drug targeting to intestinal lymphoid tissue.