Therapeutic induction of ferroptosis in tumors using PD-L1 targeting antibody nanogel conjugates.

Although programmed cell death ligand 1 (PD-L1) is best known for its role in immune suppression, tumor-intrinsic functions are emerging. Here, we report that tumor cells that express PD-L1 are sensitive to ferroptosis inducers such as imidazole ketone erastin (IKE). PD-L1 promotes ferroptosis sensitivity because it suppresses SLC7A11 expression and diminishes glutathione levels.

Polymers for Disrupting Protein-Protein Interactions: Where Are We and Where Should We Be?

Protein-protein interactions (PPIs) are central to the cellular signaling and regulatory networks that underlie many physiological and pathophysiological processes. It is challenging to target PPIs using traditional small molecule or peptide-based approaches due to the frequent lack of well-defined binding pockets at the large and flat PPI interfaces. Synthetic polymers offer an opportunity to circumvent these challenges by providing unparalleled flexibility in tuning their physiochemical properties to achieve the desired binding properties.

Antibody-Directing Antibody Conjugates (ADACs) Enabled by Orthogonal Click Chemistry for Targeted Intracellular Delivery.

Using orthogonal click chemistries for efficient nanoscale self-assembly, a new antibody-directing antibody conjugate (ADAC) nanogel is generated. In this system, one of the antibodies is displayed on the nanogel surface to specifically recognize cell-surface epitopes while the other antibody is encapsulated inside the nanogel core. The system is programmed to release the latter antibody in its functional form in the cytosolic environment of a specific cell to engage intracellular targets.

Intramolecular Electrostatic Interactions Regulate Reactivity of Zwitterionic Functionalities in Amphiphilic Assemblies.

The consequences of intramolecular ionic interactions in determining the reactivity of functional groups are of interest because they provide insights into how nature deploys seemingly reactive functionalities to be rather ubiquitous. Of specific interest are the quaternary ammonium ions in lipids. In this work, we investigate the effect of intramolecular electrostatic interactions in zwitterionic functionalities by judiciously incorporating them as leaving groups at the α-position of α,β-unsaturated ester-based lipid head groups.

Structural Determinants of Stimuli-Responsiveness in Amphiphilic Macromolecular Nano-assemblies.

Stimuli-responsive nano-assemblies from amphiphilic macromolecules could undergo controlled structural transformations and generate diverse macroscopic phenomenon under stimuli. Due to the controllable responsiveness, they have been applied for broad material and biomedical applications, such as biologics delivery, sensing, imaging, and catalysis. Understanding the mechanisms of the assembly-disassembly processes and structural determinants behind the responsive properties is fundamentally important for designing the next generation of nano-assemblies with programmable responsiveness.

Self-Assembly of Epitope-Tagged Proteins and Antibodies for Delivering Biologics to Antigen Presenting Cells.

Inspired by the immune system's own strategy for macrophage activation, we describe here a simple self-assembly strategy for generating artificial immune complexes. The built-in recognition domains in the antibody, viz. the Fab and Fc domains, are judiciously leveraged for cargo conjugation to generate the nanoassembly and macrophage targeting, respectively.

Conferring liver selectivity to a thyromimetic using a novel nanoparticle increases therapeutic efficacy in a diet-induced obesity animal model.

Optimization of metabolic regulation is a promising solution for many pathologies, including obesity, dyslipidemia, type 2 diabetes, and inflammatory liver disease. Synthetic thyroid hormone mimics-based regulation of metabolic balance in the liver showed promise but was hampered by the low biocompatibility and harmful effects on the extrahepatic axis. In this work, we show that specifically directing the thyromimetic to the liver utilizing a nanogel-based carrier substantially increased therapeutic efficacy in a diet-induced obesity mouse model, evidenced by the near-complete reversal of body weight gain, liver weight and inflammation, and cholesterol levels with no alteration in the thyroxine (T4) / thyroid stimulating hormone (TSH) axis.

Antibody Polymer Conjugates (APCs) for Active Targeted Therapeutic Delivery.

Antibody drug conjugates (ADCs) are poised to have an enormous impact on targeted nanomedicine, especially in many cancer pathologies. The reach of the current format of ADCs is limited by their low drug-to-antibody ratio (DAR) because of the associated physiochemical instabilities. Here, we design antibody polymer conjugates (APCs) as a modular strategy to utilize polymers to address ADC's shortcomings.

Multisite Labeling of Proteins Using the Ligand-Directed Reactivity of Triggerable Michael Acceptors.

Targeted modification of endogenous proteins without genetic manipulation of protein expression machinery has a range of applications from chemical biology to drug discovery. Despite being demonstrated to be effective in various applications, target-specific protein labeling using ligand-directed strategies is limited by stringent amino acid selectivity. Here, we present highly reactive ligand-directed triggerable Michael acceptors (LD-TMAcs) that feature rapid protein labeling.

Optimizing Conjugation Chemistry, Antibody Conjugation Site, and Surface Density in Antibody-Nanogel Conjugates (ANCs) for Cell-Specific Drug Delivery.

Targeted delivery of therapeutics using antibody-nanogel conjugates (ANCs) with a high drug-to-antibody ratio has the potential to overcome some of the inherent limitations of antibody-drug conjugates (ADCs). ANC platforms with simple preparation methods and precise tunability to evaluate structure-activity relationships will greatly contribute to translating this promise into clinical reality. In this work, using trastuzumab as a model antibody, we demonstrate a block copolymer-based ANC platform that allows highly efficient antibody conjugation and formulation.

Optical Fingerprinting of Dynamic Interfacial Reaction Pathways Using Liquid Crystals.

Reactions at interfaces between fluid phases are widely used to synthesize small molecules, polymers, and nanoparticles. monitoring of the underlying dynamic reaction pathways remains challenging. Liquid crystals (LCs) have been used to detect simple chemical transformations at interfaces in situations where interface-bound reactants and products trigger distinct equilibrium orientations of LCs.

Targeted Drug Delivery Using a Plug-to-Direct Antibody-Nanogel Conjugate.

Targeted drug delivery using antibody-drug conjugates has attracted great attention due to its enhanced therapeutic efficacy compared to traditional chemotherapy. However, the development has been limited due to a low drug-to-antibody ratio and laborious linker-payload optimization. Herein, we present a simple and efficient strategy to combine the favorable features of polymeric nanocarriers with antibodies to generate an antibody-nanogel conjugate (ANC) platform for targeted delivery of cytotoxic agents.

Colorimetric Cotton Swab for Viral Protease Detection.

Reporting the activity of a specific viral protease remains an acute need for rapid point-of-care detection strategies that can distinguish active infection from a resolved infection. In this work, we present a simple colorimetric approach for reporting the activity of a specific viral protease through direct color conversion on a cotton swab, which has the potential to be extended to detect the corresponding virus. We use SARS-CoV-2 viral protease as a proof-of-concept model system.

Thiol-Disulfide Exchange as a Route for Endosomal Escape of Polymeric Nanoparticles.

Endosomal entrapment has remained the major bottleneck for cytosolic delivery of nanoparticle-based delivery systems. Uncovering fundamentally new pathways for endosomal escape is therefore highly sought. Herein, we report that disulfide bonds can enhance endosomal escape through contacts with cellular exofacial thiols, in addition to facilitating cellular uptake.

Charge-Conversion Strategies for Nucleic Acid Delivery.

Nucleic acids are now considered as one of the most potent therapeutic modalities, as their roles go beyond storing genetic information and chemical energy or as signal transducer. Attenuation or expression of desired genes through nucleic acids have profound implications in gene therapy, gene editing and even in vaccine development for immunomodulation. Although nucleic acid therapeutics bring in overwhelming possibilities towards the development of molecular medicines, there are significant loopholes in designing and effective translation of these drugs into the clinic.

Multiplexed Analysis of the Cellular Uptake of Polymeric Nanocarriers.

Polymeric nanocarriers (PNCs) are versatile drug delivery vehicles capable of delivering a variety of therapeutics. Quantitatively monitoring their uptake in biological systems is essential for realizing their potential as next-generation delivery systems; however, existing quantification strategies are limited due to the challenges of detecting polymeric materials in complex biological samples. Here, we describe a metal-coded mass tagging approach that enables the multiplexed quantification of the PNC uptake in cells using mass spectrometry (MS).

What's Next after Lipid Nanoparticles? A Perspective on Enablers of Nucleic Acid Therapeutics.

Recent success of mRNA-based COVID-19 vaccines have bolstered the strength of nucleic acids as a therapeutic platform. The number of new clinical trial candidates is skyrocketing with the potential to address many unmet clinical needs. Despite advancements in other aspects, the systemic delivery of nucleic acids to target sites remains a major challenge.

Controlling Liquid Crystal Configuration and Phase Using Multiple Molecular Triggers.

Liquid crystals are able to transform a local molecular interaction into a macroscopic change of state, making them a valuable "smart" material. Here, we investigate a novel polymeric amphiphile as a candidate for molecular triggering of liquid crystal droplets in aqueous background. Using microscopy equipped with crossed polarizers and optical tweezers, we find that the monomeric amphiphile is able to trigger both a fast phase change and then a subsequent transition from nematic to isotropic.

Evaluation of Cellular Targeting by Fab' vs Full-Length Antibodies in Antibody-Nanoparticle Conjugates (ANCs) Using CD4 T-cells.

Targeted delivery of chemotherapeutic drugs can improve their therapeutic efficiency by localizing their toxic effects at the diseased site. This is often achieved either by direct conjugation of drugs to antibodies targeting overexpressed receptors on cancer cells (antibody-drug conjugates/ADCs) or by conjugating antibodies to nanoparticles bearing drugs (antibody-nanoparticle conjugates/ANCs). Here, we report a platform for utilizing hinge cysteines on antigen-binding fragment (Fab') of an anti-CD4 antibody for site-specific conjugation to nanoparticles giving rise to anti-CD4 Fab'-nanoparticle conjugates (Fab'-NCs).

Influence of Polymer Structure and Architecture on Drug Loading and Redox-Triggered Release.

Disulfide cross-linked nanoassemblies have attracted considerable attention as a drug delivery vehicle due to their responsiveness to the natural redox gradient in biology. Fundamentally understanding the factors that influence the drug loading capacity, encapsulation stability, and precise control of the liberation of encapsulated cargo would be profoundly beneficial to redox-responsive materials. Reported herein are block copolymer (BCP)-based self-cross-linked nanogels, which exhibit high drug loading capacity, high encapsulation stability, and controllable release kinetics.

Three-Component Dynamic Covalent Chemistry: From Janus Small Molecules to Functional Polymers.

A new multicomponent reaction involving 2-ydroxybenzaldehyde, mine, and 2-ercaptobenzaldehyde (HAM reaction) has been developed and applied to multicomponent polymerization and controlled radical polymerization for the construction of random and block copolymers. This chemistry features mild reaction conditions, high yield, simple isolation, and water as the only byproduct. With the advantages of the distinct nucleophilicity of thiol and hydroxyl groups, the chemistry could be used for stepwise labeling and modifications on primary amines.

Multichannel dual protein sensing using amphiphilic supramolecular assemblies.

Protein sensing strategies have implications in detection of many human pathologies. Here, a supramolecular strategy for sensing two different proteins using a multichannel readout approach is outlined. Protein-ligand binding or enzymatic cleavage can both be programmed to induce supramolecular disassembly, which leads to fluorescence enhancement aggregation-induced emission (AIE), protein-induced fluorescence enhancement (PIFE), or disassembly-induced fluorescence enhancement (DIFE).

Toward Chemotactic Supramolecular Nanoparticles: From Autonomous Surface Motion Following Specific Chemical Gradients to Multivalency-Controlled Disassembly.

Nature designs chemotactic supramolecular structures that can selectively bind specific groups present on surfaces, autonomously scan them moving along density gradients, and react once a critical concentration is encountered. Since such properties are key in many biological functions, these also offer inspirations for designing artificial systems capable of similar bioinspired autonomous behaviors. One approach is to use soft molecular units that self-assemble in an aqueous solution generating nanoparticles (NPs) that display specific chemical groups on their surface, enabling multivalent interactions with complementarily functionalized surfaces.