The Promise and Potential of Metal-Organic Frameworks and Covalent Organic Frameworks in Vaccine Nanotechnology

The immune system’s complexity and ongoing evolutionary struggle against deleterious pathogens underscore the value of vaccination technologies, which have been bolstering human immunity for over two centuries. Despite noteworthy advancements over these 200 years, three areas remain recalcitrant to improvement owing to the environmental instability of the biomolecules used in vaccines—the challenges of formulating them into controlled release systems, their need for constant refrigeration to avoid loss of efficacy, and the requirement that they be delivered via needle owing to gastrointestinal incompatibility. Nanotechnology, particularly Metal-Organic Frameworks (MOFs) and Covalent Organic Frameworks (COFs), has emerged as a promising avenue for confronting these challenges, presenting a new frontier in vaccine development. Although these materials have been widely explored in the context of drug delivery, imaging, and cancer immunotherapy, their role in immunology and vaccine-related applications is a recent yet rapidly developing field. This review seeks to elucidate the prospective use of MOFs and COFs for biomaterial stabilization, eliminating the necessity for cold chains, enhancing antigen potency as adjuvants, and potentializing needle-free delivery of vaccines. It provides an expansive and critical viewpoint on this rapidly evolving field of research and emphasizes the vital contribution of chemists in driving further advancements

Rip It, Stitch It, Click It: A Chemist’s Guide to VLP Manipulation

Viruses are some of nature’s most ubiquitous self-assembled molecular containers. Evolutionary pressures have created some incredibly robust, thermally and enzymatically resistant containers to transport delicate genetic information safely. Virus-like particles (VLPs) are human-engineered non-infectious systems that inherit the parent virus’ ability to self-assemble under controlled conditions while being non-infectious. VLPs and plant-based viral nanoparticles are becoming increasingly popular in medicine as their self-assembly properties are exploitable for applications ranging from diagnostic tools to targeted drug delivery. Understanding the basic structure and principles underlying the assembly of higher-order structures has allowed researchers to disassemble (rip it), functionalize (click it), and reassemble (stitch it) these systems on demand. This review focuses on the current toolbox of strategies developed to manipulate these systems by ripping, stitching, and clicking to create new technologies in the biomedical space

Biolistic Delivery of MOF-Protected Liposomes

Needle-and-syringe-based delivery has been the commercial standard for vaccine administration to date. With worsening medical personnel availability, increasing biohazard waste production, and the possibility of cross-contamination, we explore the possibility of biolistic delivery as an alternate skin-based delivery route. Delicate formulations like liposomes are inherently unsuitable for this delivery model as they are delicate biomaterials incapable of withstanding shear stress. When encapsulated within a crystalline and rigid coating made of zeolitic imidazolate frameworks, the liposomes are not only protected from thermal stress but also shear stress. The protection from shear stress is crucial, especially for formulations with cargo encapsulated inside the lumen of the liposomes. Moreover, the coating provides the liposomes a solid, rigid exterior which allows the particles to penetrate the tissue model and porcine tissue effectively

Zeolitic Imidazolate Framework Nanoencapsulation of CpG for Stabilization and Enhancement of Immunoadjuvancy

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 2 immunogenicity of these proteinaceous therapeutics. In this work we show that MOFs can also be used to protect the ssDNA oligomer, CpG, to increase its immunoadjuvancy. By encapsulating phosphodiester CpG in the zinc-based MOF, ZIF-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 nano-sized MOF for the optimization of particulate delivery of immunoadjuvants to maximize immune activation

PhotothermalPhage: A Virus-Based Photothermal Therapeutic Agent

ABSTRACT: 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 Photothermal Phage. 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

A Scalable Synthesis of Adjuvanting Antigen Depots Based on Met-al-Organic Frameworks

Vaccines have saved countless lives by preventing and even irradicating infectious diseases. Commonly used subunit vaccines comprising one or multiple recombinant proteins isolated from a pathogen demonstrate a better safety profile than live or attenuated vaccines. However, the immunogenicity of these vaccines is weak, and therefore, subunit vaccines require a series of doses to achieve sufficient immunity against the pathogen. Here, we show that the biomimetic mineralization of the inert model antigen, ovalbumin (OVA), in zeolitic imidazolate framework-8 (ZIF-8) significantly improves the humoral immune response over three bolus doses of OVA (OVA 3×). Encapsulation of OVA in ZIF-8 (OVA@ZIF) demonstrated higher serum antibody titers against OVA than OVA 3×. OVA@ZIF vaccinated mice displayed higher populations of germinal center (GC) B cells and IgG1+ GC B cells as opposed to OVA 3×, indicative of class-switching recombination. We show that the mechanism of this phenomenon is at least partly owed to the metalloimmunological effects of the zinc metal as well as the sustained release of OVA from the ZIF-8 composite. The system acts as an antigen reservoir for antigen-presenting cells to traffic into the draining lymph node, enhancing the humoral response. Lastly, our model system OVA@ZIF is produced quickly at the gram scale in a laboratory setting, sufficient for up to 20,000 vaccine doses

Carrier Gas Triggered Controlled Biolistic Delivery of DNA and Protein Therapeutics from Metal-Organic Frameworks

Abstract: The efficacy and specificity of protein, DNA, and RNA-based drugs have made them popular in the clinic; however, their susceptibility to environmental stressors adds significant challenges to formulating biomacromolecules into delivery systems where the kinetics of release can be tuned. Further, these drugs are often delivered via injection, which requires skilled medical personnel and produces biohazardous waste. Here, we report an approach that allows for the controlled delivery of DNA and protein therapeutics to allow for either burst or slow-release kinetics without altering the formulation; further, we show we can deliver these materials into the tissues of very different organisms without the use of needles. We show that biomaterials encapsulated within the highly porous metal-organic Framework ZIF-8 are stable as a powder formulation that can be shot into tissue with a low-cost gas-powered “MOF-Jet” for direct delivery into living tissues of plants and animals and the release of the biomaterials can be controlled by judiciously choosing the compressed gas used in the gun. Many MOFs, including ZIF-8, are acid labile and readily dissolve at low pH. When CO2 is used as the carrier gas to shoot MOFs into moist tissue, we show that we can create a transient and weakly acidic local environment that causes the near-instantaneous release of the biomolecules. Conversely, when air is used, the MOF is delivered into tissue and degrades slowly over a week, releasing biomolecules. This innovation represents the first example of biolistic-mediated controlled delivery of biomolecules with ZIF-8 and provides a powerful tool for fundamental and applied plant and animal sciences research