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Abstract 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. This generates non-aqueous, fluorine-based liquid protein formulations that biochemically rigidify protein structure to yield thermally stable biologics at extreme temperatures (up to 90 °C). These non-aqueous formulations are impervious to contamination by microorganismal pathogens, degradative enzymes, and environmental impurities, and display comparable pre-clinical pharmacokinetics and safety profiles to standard saline protein samples. As a result, we deliver a fluorochemical formulation paradigm that may limit the need for cold chain logistics of protein reagents and biopharmaceuticals. 

Abstract Non‐invasive imaging modalities that identify rupture‐prone atherosclerotic plaques hold promise to improve patient risk stratification and advance early intervention strategies. Here, phase‐changing peptide nanoemulsions are developed as theranostic contrast agents for synchronous ultrasound detection and therapy of at‐risk atherosclerotic lesions. By targeting lipids within atherogenic foam cells, and exploiting characteristic features of vulnerable plaques, these nanoemulsions preferentially accumulate within lesions and are retained by intraplaque macrophages. It is demonstrated that acoustic vaporization of intracellular nanoemulsions promotes lipid efflux from foam cells and generates echogenic microbubbles that provide contrast‐enhanced ultrasound identification of lipid‐rich anatomical sites. In Doppler mode, stably oscillating peptide nanoemulsions induce random amplitude and phase changes of the echo wave to generate transient color imaging features, referred to as ‘twinkling’. Importantly, acoustic twinkling is unique to these peptide emulsions, and not observed from endogenous tissue bubble nuclei, generating diagnostic features that offer unprecedented spatial precision of lesion identification in 3D. 

Abstract Interfacial self‐assembly describes the directed organization of molecules and colloids at phase boundaries. Believed to be fundamental to the inception of primordial life, interfacial assembly is exploited by a myriad of eukaryotic and prokaryotic organisms to execute physiologic activities and maintain homeostasis. Inspired by these natural systems, chemists, engineers, and materials scientists have sought to harness the thermodynamic equilibria at phase boundaries to create multi‐dimensional, highly ordered, and functional nanomaterials. Recent advances in our understanding of the biophysical principles guiding molecular assembly at gas–solid, gas–liquid, solid–liquid, and liquid–liquid interphases have enhanced the rational design of functional bio‐nanomaterials, particularly in the fields of biosensing, bioimaging and biotherapy. Continued development of non‐canonical building blocks, paired with deeper mechanistic insights into interphase self‐assembly, holds promise to yield next generation interfacial bio‐nanomaterials with unique, and perhaps yet unrealized, properties. This article is categorized under:Nanotechnology Approaches to Biology > Nanoscale Systems in BiologyTherapeutic Approaches and Drug Discovery > Emerging Technologies 

Abstract The human colon is home to trillions of microorganisms that modulate gastrointestinal physiology. The understanding of how this gut ecosystem impacts human health, although evolving, is slowed by the lack of accessible tools suitable to studying complex host‐mucus‐microbe interactions. Here, a synthetic gel‐like material capable of recapitulating the varied structural, mechanical, and biochemical profiles of native human colonic mucus is reported to develop compositionally simple microbiome screening platforms with utility in microbiology and drug discovery. The viscous fibrillar material is realized through templated assembly of a fluorine‐rich amino acid at liquid‐liquid interphases. The fluorine‐assisted mucus surrogate (FAMS) can be decorated with mucins to serve as a habitat for microbial colonization and integrated with human colorectal cells to generate artificial mucosae, referred to as a microbiome organoid. Notably, FAMS are made with inexpensive and commercially available materials and can be generated using simple protocols and standard laboratory hardware. As a result, this platform can be broadly incorporated into various laboratory settings to advance probiotic research and inform in vivo approaches. If implemented into high throughput screening approaches, FAMS may represent a valuable tool to study compound metabolism and gut permeability, with an exemplary demonstration of this utility presented here. 

Abstract 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. Notably, we show that the lead compound, perfluorononanoic acid, is 10⁶times more potent in inducing non‐native protein secondary structure in select proteins than is the well‐known helix inducer trifluoroethanol, and also significantly enhances the cellular uptake of complexed proteins. These findings could advance the rational design of fluorinated proteins, inform on potential modes of toxicity for perfluoroalkyl substances, and guide the development of fluorine‐modified biologics with desirable functional properties for drug discovery and delivery applications. 

Abstract 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. Here, we rationally design fibrinogen‐mimicking fluoropeptide nanoemulsions, or nanopeptisomes (NPeps), that allow contrast‐enhanced ultrasound imaging of thrombi and synchronous inhibition of clot growth. The theranostic duality of NPeps is imparted via their intrinsic binding to integrins overexpressed on platelets activated during coagulation. The platelet‐bound nanoemulsions can be vaporized and oscillate in an applied acoustic field to enable contrast‐enhanced Doppler ultrasound detection of thrombi. Concurrently, nanoemulsions bound to platelets competitively inhibit secondary platelet–fibrinogen binding to disrupt further clot growth. Continued development of this synchronous theranostic platform may open new opportunities for image‐guided, non‐invasive, interventions for DVT and other vascular diseases. 

Abstract Nature has evolved several elegant strategies to organize inert building blocks into adaptive supramolecular structures. Favored among these is interfacial self‐assembly, where the unique environment of liquid–liquid junctions provides structural, kinetic, thermodynamic, and chemical properties that are distinct from the bulk solution. Here, antithetical fluorous–water interfaces are exploited to guide the assembly of non‐canonical fluorinated amino acids into crystalline mechanomorphogenic films. That is, the nanoscale order imparted by this strategy yields self‐healing materials that can alter their macro‐morphology depending on exogenous mechanical stimuli. Additionally, like natural biomolecules, organofluorine amino acid films respond to changes in environmental ionic strength, pH, and temperature to adopt varied secondary and tertiary states. Complementary biophysical and biochemical studies are used to develop a model of amino acid packing to rationalize this bioresponsive behavior. Finally, these films show selective permeability, capturing fluorous compounds while allowing the free diffusion of water. These unique capabilities are leveraged in an exemplary application of the technology to extract perfluoroalkyl substances from contaminated water samples rapidly. Continued exploration of these materials will advance the understanding of how interface‐templated and fluorine‐driven assembly phenomenon a can be co‐utilized to design adaptive molecular networks and living matter. 

Abstract 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 macro‐supramolecular states that potentiate high‐ordered organization into material scaffolds. These fluorine‐tailored peptide assemblies employ the unique fluorous environment to boost biofunctionality for a broad range of applications, from drug delivery to antibacterial coatings. This review provides foundational tactics for peptide fluorination and discusses the utility of these fluorous‐directed hierarchical structures as material platforms in diverse biomedical applications.