Drug delivery is commonly thought of as the performance of a drug in vivo. Rather, the process of drug delivery can comprise of the journey of the drug from manufacturer to clinic, clinic to patient, and patient to disease. Each step of the journey includes hurdles that must be overcome for the therapeutic to be successful. Recent developments in proteinaceous therapeutics have made the successful completion of this journey even more important because of the relatively fragile nature of proteins in a drug delivery context. Polymers have been demonstrated to be an effective complement to proteinaceous therapeutics throughout this journey owing to their flexibility in design and function. During transit from manufacturer to clinic, the proteinaceous drug is threatened by denaturation at elevated temperatures. Polymers can help improve the thermal stability of the drug at ambient shipping conditions, thereby reducing the need for an expensive cold chain to preserve its bioactivity. Upon arrival at the clinic, the drug must be reconstituted into a suitable formulation that can be introduced into the patient. Unfortunately, traditional drug formulations relying on oral administration are generally not suitable for proteinaceous drugs owing to the hostile environment of the stomach. Other traditional methods of drug administration-like hypodermic injections-frequently suffer from low patient compliance. Polymers have been explored to design drug formulations suitable for alternative methods of administration. Upon entry into the body, proteinaceous drugs are at risk for identification, destruction, and excretion by the immune system. Polymers can help drugs reprogram immune system response and, in some cases, elicit a synergistic immune response. The next phase of research on protein-polymer-based therapeutics encourages a holistic effort to design systems that can survive each stage of the drug delivery journey.

The increasing rate of resistance of bacterial infection against antibiotics requires next generation approaches to fight potential pandemic spread. The development of vaccines against pathogenic bacteria has been difficult owing, in part, to the genetic diversity of bacteria. Hence, there are many potential target antigens and little a priori knowledge of which antigen/s will elicit protective immunity. The painstaking process of selecting appropriate antigens could be avoided with whole-cell bacteria; however, whole-cell formulations typically fail to produce long-term and durable immune responses. These complications are one reason why no vaccine against any type of pathogenic E. coli has been successfully clinically translated. As a proof of principle, we demonstrate a method to enhance the immunogenicity of a model pathogenic E. coli strain by forming a slow releasing depot. The E. coli strain CFT073 was biomimetically mineralized within a metal–organic framework (MOF). This process encapsulates the bacteria within 30 min in water and at ambient temperatures. Vaccination with this formulation substantially enhances antibody production and results in significantly enhanced survival in a mouse model of bacteremia compared to standard inactivated formulations.

Icosahedral virus-like particles (VLPs) derived from bacteriophages Qβ and PP7 encapsulating small-ultra red fluorescent protein (smURFP) were produced using a versatile supramolecualr capsid dissassemble-reassemble approach. The generated fluorescent VLPs display identical structural properties to their non-fluorescent analogs. Encapsulated smURFP shows indistinguishable photochemical properties to its unencapsulated counterpart, exhibits outstanding stability towards pH, and produces bright in vitro images following phagocytosis by macrophages. In vivo imaging allows biodistribution to be imaged at different time points. Ex vivo imaging of intravenously administered encapsulated smURFP reveleas localization in the liver and kidneys after 2 h blood circulation and substantial elimination after 16 h of imaging highlighting the potential application of these constructs as non-invasive in vivo imaging agents.

Supramolecular/macromolecular organic radical contrast agents (smORCAs) overcome many of the limitations of nitroxide radicals for use in magnetic resonance imaging in vivo like poor stability and weak contrast.

Artificial native-like lipid bilayer systems constructed from phospholipids assembling into unilamellar liposomes allow the reconstitution of detergent-solubilized transmembrane proteins into supramolecular lipid-protein assemblies called proteoliposomes, which mimic cellular membranes. Stabilization of these complexes remains challenging because of their chemical composition, the hydrophobicity and structural instability of membrane proteins, and the lability of interactions between protein, detergent, and lipids within micelles and lipid bilayers. In this work we demonstrate that metastable lipid, protein-detergent, and protein-lipid supramolecular complexes can be successfully generated and immobilized within zeolitic-imidazole framework (ZIF) to enhance their stability against chemical and physical stressors. Upon immobilization in ZIF bio-composites, blank liposomes, and model transmembrane metal transporters in detergent micelles or embedded in proteoliposomes resist elevated temperatures, exposure to chemical denaturants, aging, and mechanical stresses. Extensive morphological and functional characterization of the assemblies upon exfoliation reveal that all these complexes encapsulated within the framework maintain their native morphology, structure, and activity, which is otherwise lost rapidly without immobilization.

Virus-like particles (VLPs) are multifunctional nanocarriers that mimic the architecture of viruses. They can serve as a safe platform for specific functionalization and immunization, which provides benefits in a wide range of biomedical applications. In this work, a new generation immunophotothermal agent is developed that adjuvants photothermal ablation using a chemically modified VLP called bacteriophage Qβ. The design is based on the conjugation of near-infrared absorbing croconium dyes to lysine residues located on the surface of Qβ, which turns it to a powerful NIR-absorber called PhotothermalPhage. This system can generate more heat upon 808 nm NIR laser radiation than free dye and possesses a photothermal efficiency comparable to gold nanostructures, yet it is biodegradable and acts as an immunoadjuvant combined with the heat it produces. The synergistic combination of thermal ablation with the mild immunogenicity of the VLP leads to effective suppression of primary tumors, reduced lung metastasis, and increased survival time.

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Metal–organic frameworks (MOFs) have been used to improve vaccine formulations by stabilizing proteins and protecting them against thermal degradation. This has led to increased immunogenicity of these proteinaceous therapeutics. In this work, we show that MOFs can also be used to protect the single-stranded DNA oligomer CpG to increase its immunoadjuvancy. By encapsulation of the phosphodiester CpG in the zinc-based MOF, zeolitic imidazolate framework-8, the DNA oligomer is protected from nuclease degradation and exhibits improved cellular uptake. As a result, we have been able to achieve drastically enhanced B-cell activation in splenocyte cultures comparable to the current state-of-the-art phosphorothioate CpG. Furthermore, we have made a direct comparison of micro- and nanosized MOFs for optimization of the particulate delivery of immunoadjuvants to maximize immune activation.