Heat stable and intrinsically sterile liquid protein formulations.

Over 80% of biologic drugs, and 90% of vaccines, require temperature-controlled conditions throughout the supply chain to minimize thermal inactivation and contamination. This cold chain is costly, requires stringent oversight, and is impractical in remote environments. Here, we report chemical dispersants that non-covalently solvate proteins within fluorous liquids to alter their thermodynamic equilibrium and reduce conformational flexibility.

Bactericidal Metal-Organic Gallium Frameworks - Synthesis to Application.

Gallium, a trace metal not found in its elemental form in nature, has garnered significant interest as a biocide, given its ability to interfere with iron metabolism in bacteria. Consequently, several gallium compounds have been developed and studied for their antimicrobial properties but face challenges of poor solubility and formulation for delivery. Organizing the metal into three-dimensional, hybrid scaffolds, termed metal-organic frameworks (MOFs), is an emerging platform with potential to address many of these limitations.

Decoupling Fluorous Protein Coatings Yield Heat-Stable and Intrinsically Sterile Bioformulations.

Thermal inactivation is a major bottleneck to the scalable production, storage, and transportation of protein-based reagents and therapies. Failures in temperature control both compromise protein bioactivity and increase the risk of microorganismal contamination. Herein, we report the rational design of fluorochemical additives that promiscuously bind to and coat the surfaces of proteins to enable their stable dispersion within fluorous solvents.

Real-Time, In Situ Imaging of Macrophages via Phase-Change Peptide Nanoemulsions.

Macrophages are specialized phagocytes that play central roles in immunity and tissue repair. Their diverse functionalities have led to an evolution of new allogenic and autologous macrophage products. However, realizing the full therapeutic potential of these cell-based therapies requires development of imaging technologies that can track immune cell migration within tissues in real-time.

The manifold role of octapeptide repeats in prion protein assembly.

Prion protein misfolding is associated with fatal neurodegenerative disorders such as kuru, Creutzfeldt-Jakob disease, and several animal encephalopathies. While the C-terminal 106-126 peptide has been well studied for its role in prion replication and toxicity, the octapeptide repeat (OPR) sequence found within the N-terminal domain has been relatively under explored. Recent findings that the OPR has both local and long-range effects on prion protein folding and assembly, as well as its ability to bind and regulate transition metal homeostasis, highlights the important role this understudied region may have in prion pathologies.

Deciphering the Mechanistic Basis for Perfluoroalkyl-Protein Interactions.

Although rarely used in nature, fluorine has emerged as an important elemental ingredient in the design of proteins with altered folding, stability, oligomerization propensities, and bioactivity. Adding to the molecular modification toolbox, here we report the ability of privileged perfluorinated amphiphiles to noncovalently decorate proteins to alter their conformational plasticity and potentiate their dispersion into fluorous phases. Employing a complementary suite of biophysical, in-silico and in-vitro approaches, we establish structure-activity relationships defining these phenomena and investigate their impact on protein structural dynamics and intracellular trafficking.

Heparin-Peptide Nanogranules for Thrombosis-Actuated Anticoagulation.

Despite nearly a century of clinical use as a blood thinner, heparin's rapid serum clearance and potential to induce severe bleeding events continue to urge the development of more effective controlled delivery strategies. Subcutaneous depots that steadily release the anticoagulant into circulation represent a promising approach to reducing overdose frequency, sustaining therapeutic concentrations of heparin in plasma, and prolonging anticoagulant activity in a safe and effective manner. Subcutaneously deliverable heparin-peptide nanogranules that allow for long-lasting heparin bioavailability in the circulatory system, while enabling on-demand activation of heparin's anticoagulant effects in the thrombus microenvironment, are reported.

Biomaterials-Enabled Antithrombotics: Recent Advances and Emerging Strategies.

Antithrombotic and thrombolytic therapies are used to prevent, treat, and remove blood clots in various clinical settings, from emergent to prophylactic. While ubiquitous in their healthcare application, short half-lives, off-target effects, overdosing complications, and patient compliance continue to be major liabilities to the utility of these agents. Biomaterials-enabled strategies have the potential to comprehensively address these limitations by creating technologies that are more precise, durable, and safe in their antithrombotic action.

Inhalable SARS-CoV-2 Mimetic Particles Induce Pleiotropic Antigen Presentation.

Coronavirus disease 2019 (Covid-19) has caused over 5.5 million deaths worldwide, and viral mutants continue to ravage communities with limited access to injectable vaccines or high rates of vaccine hesitancy. Inhalable vaccines have the potential to address these distribution and compliance issues as they are less likely to require cold storage, avoid the use of needles, and can elicit localized immune responses with only a single dose.

Fluorinated peptide biomaterials.

Fluorinated compounds, while rarely used by nature, are emerging as fundamental ingredients in biomedical research, with applications in drug discovery, metabolomics, biospectroscopy, and, as the focus of this review, peptide/protein engineering. Leveraging the fluorous effect to direct peptide assembly has evolved an entirely new class of organofluorine building blocks from which unique and bioactive materials can be constructed. Here, we discuss three distinct peptide fluorination strategies used to design and induce peptide assembly into nano-, micro-, and macrosupramolecular states that potentiate high-ordered organization into material scaffolds.

Ultrasound-Responsive Nanopeptisomes Enable Synchronous Spatial Imaging and Inhibition of Clot Growth in Deep Vein Thrombosis.

Deep vein thrombosis (DVT) is a life-threatening blood clotting condition that, if undetected, can cause deadly pulmonary embolisms. Critical to its clinical management is the ability to rapidly detect, monitor, and treat thrombosis. However, current diagnostic imaging modalities lack the resolution required to precisely localize vessel occlusions and enable clot monitoring in real time.

Extracellular matrix-inspired inhalable aerogels for rapid clearance of pulmonary tuberculosis.

Tuberculosis (TB) remains a leading cause of death from a single infectious agent, and limiting the spread of multidrug-resistant TB (MDR-TB) is now an urgent global health priority. Essential to the persistence of this disease is the ability of Mycobacterium tuberculosis (Mtb) to circumvent host defenses by infecting lung macrophages to create a cellular niche for its survival and proliferation. This has urged the development of new therapeutic strategies that act through mechanisms distinct from conventional antibiotics, and thus are effective against MDR bacteria, while being able to efficiently kill persister Mtb cells in infected host macrophages.

Peptide functionalized liposomes for receptor targeted cancer therapy.

Most clinically approved cancer therapies are potent and toxic small molecules that are limited by severe off-target toxicities and poor tumor-specific localization. Over the past few decades, attempts have been made to load chemotherapies into liposomes, which act to deliver the therapeutic agent directly to the tumor. Although liposomal encapsulation has been shown to decrease toxicity in human patients, reliance on passive targeting via the enhanced permeability and retention (EPR) effect has left some of these issues unresolved.

Tuning the Interfacial Properties of Fluorous Colloids Toward Ultrasound Programmable Bioactivity.

Liquid-in-liquid emulsions are kinetically stable colloids that undergo liquid-to-gas phase transitions in response to thermal or acoustic stimuli. Perfluorocarbons (PFCs) are preferred species as their highly fluorinated nature imparts unique properties that are unparalleled by nonfluorinated counterparts. However, traditional methods to prepare PFC emulsions lack the ability to precisely tune the thermodynamic stability of the fluorous-water interphase and consequently control their vaporization behavior.

Pathogen-specific antimicrobials engineered de novo through membrane-protein biomimicry.

Precision antimicrobials aim to kill pathogens without damaging commensal bacteria in the host, and thereby cure disease without antibiotic-associated dysbiosis. Here we report the de novo design of a synthetic host defence peptide that targets a specific pathogen by mimicking key molecular features of the pathogen's channel-forming membrane proteins. By exploiting physical and structural vulnerabilities within the pathogen's cellular envelope, we designed a peptide sequence that undergoes instructed tryptophan-zippered assembly within the mycolic acid-rich outer membrane of Mycobacterium tuberculosis to specifically kill the pathogen without collateral toxicity towards lung commensal bacteria or host tissue.

Re-engineering Antimicrobial Peptides into Oncolytics Targeting Drug-Resistant Ovarian Cancers.

Introduction: Bacteria and cancer cells share a common trait-both possess an electronegative surface that distinguishes them from healthy mammalian counterparts. This opens opportunities to repurpose antimicrobial peptides (AMPs), which are cationic amphiphiles that kill bacteria by disrupting their anionic cell envelope, into anticancer peptides (ACPs). To test this assertion, we investigate the mechanisms by which a pathogen-specific AMP, originally designed to kill bacterial Tuberculosis, potentiates the lytic destruction of drug-resistant cancers and synergistically enhances chemotherapeutic potency.

Supramolecular Peptide Assemblies as Antimicrobial Scaffolds.

Antimicrobial discovery in the age of antibiotic resistance has demanded the prioritization of non-conventional therapies that act on new targets or employ novel mechanisms. Among these, supramolecular antimicrobial peptide assemblies have emerged as attractive therapeutic platforms, operating as both the bactericidal agent and delivery vector for combinatorial antibiotics. Leveraging their programmable inter- and intra-molecular interactions, peptides can be engineered to form higher ordered monolithic or co-assembled structures, including nano-fibers, -nets, and -tubes, where their unique bifunctionalities often emerge from the supramolecular state.

Ultrasound-Guided Cytosolic Protein Delivery Transient Fluorous Masks.

The inability to spatiotemporally guide proteins in tissues and efficiently deliver them into cells remains a key barrier to realizing their full potential in precision medicine. Here, we report ultrasound-sensitive fluoro-protein nanoemulsions which can be acoustically tracked, guided, and activated for on-demand cytosolic delivery of proteins, including antibodies, using clinically relevant diagnostic ultrasound. This advance is accessed through the discovery of a family of fluorous tags, or FTags, that transiently mask proteins to mediate their efficient dispersion into ultrasound-sensitive liquid perfluorocarbons, a phenomenon akin to dissolving an egg in liquid Teflon.

Discovery of antitumor lectins from rainforest tree root transcriptomes.

Glycans are multi-branched sugars that are displayed from lipids and proteins. Through their diverse polysaccharide structures they can potentiate a myriad of cellular signaling pathways involved in development, growth, immuno-communication and survival. Not surprisingly, disruption of glycan synthesis is fundamental to various human diseases; including cancer, where aberrant glycosylation drives malignancy.

Clinical characteristics associated with depression or anxiety among patients presenting for knee surgery.

Background: Preoperative depression and anxiety in patients undergoing surgery have been shown to be associated with increased postoperative complications, decreased functional improvement, and long-term dissatisfaction. The purpose of this prospective study was to measure the relationship between a diagnosis of depression or anxiety and Patient-Reported Outcomes Measurement Information System (PROMIS) domains, as well as determine which preoperative factors are associated with depression or anxiety in patients undergoing knee surgery. We hypothesized that preoperative depression and/or anxiety would be associated with worse preoperative pain, function, and general health status.

Rapid fabrication of precise high-throughput filters from membrane protein nanosheets.

Biological membranes are ideal for separations as they provide high permeability while maintaining high solute selectivity due to the presence of specialized membrane protein (MP) channels. However, successful integration of MPs into manufactured membranes has remained a significant challenge. Here, we demonstrate a two-hour organic solvent method to develop 2D crystals and nanosheets of highly packed pore-forming MPs in block copolymers (BCPs).

Preoperative Expectations of Patients Undergoing Knee Surgery.

There is limited validated data regarding the relationship between preoperative expectations and patient-reported outcomes (PROs) in patients undergoing knee surgery. The purpose of this study was to (1) assess the preoperative expectations of patients undergoing knee surgery and (2) determine the relationship between preoperative patient demographics, PROs, and preoperative patient expectations. We hypothesized that younger patients with worse function and worse general health status would have greater expectations of knee surgery.

Identification of a mechanogenetic link between substrate stiffness and chemotherapeutic response in breast cancer.

Mechanical feedback from the tumor microenvironment regulates an array of processes underlying cancer biology. For example, increased stiffness of mammary extracellular matrix (ECM) drives malignancy and alters the phenotypes of breast cancer cells. Despite this link, the role of substrate stiffness in chemotherapeutic response in breast cancer remains unclear.