A scalable synthesis of adjuvanting antigen depots based on metal–organic frameworks

Ehrman, Ryanne N.; Brohlin, Olivia R.; Wijesundara, Yalini H.; Kumari, Sneha; Trashi, Orikeda; Howlett, Thomas S.; Trashi, Ikeda; Herbert, Fabian C.; Raja, Arun; Koirala, Shailendra; Tran, Nancy; Al-Kharji, Noora M.; Tang, Wendy; Senarathna, Milinda C.; Hagge, Laurel M.; Smaldone, Ronald A.; Gassensmith, Jeremiah J.

doi:10.1039/d3sc06734c

Cited by 11 publications

(6 citation statements)

References 69 publications

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“…154 It is important to understand, however, that the FDA-approved adjuvant alum is more cytotoxic than ZIF-8 and that the same approximate dose used to vaccinate mice would be used in humans, which are comparatively gigantic. 227 The material needed is typically only 10−50 μg of antigen, meaning the MOF needed is typically well below a milligram. Further, vaccines are not injected into the blood, and most of their degradation occurs at the injection site.…”

Section: Limitations and Unrealized Advantages Of Using Reticular Pla...mentioning

confidence: 99%

“…This toxicity is aided by the ability of MOFs to escape the endo/lysosome, which enables cytosolic delivery of their metals . It is important to understand, however, that the FDA-approved adjuvant alum is more cytotoxic than ZIF-8 and that the same approximate dose used to vaccinate mice would be used in humans, which are comparatively gigantic . The material needed is typically only 10–50 μg of antigen, meaning the MOF needed is typically well below a milligram.…”

Section: Limitations and Unrealized Advantages Of Using Reticular Pla...mentioning

confidence: 99%

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

Wijesundara,

Howlett,

Kumari

et al. 2024

Chem. Rev.

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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. CONTENTS 1. Introduction to Vaccines and Immuno-Therapeutics and Current Limitations in the Landscape of Vaccine Technology 3013 2. Unique Structural Features of MOFs/COFs 3015 3. Advantages of Using MOFs/COFs To Fill the Gap in Current Vaccine Technology 3017 3.1. Thermodynamic Stability of MOFs 3017 3.2. Kinetic Lability 3019 3.3. Functional Modification 3019 3.4. Needle-Free Delivery 3019 4.

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Section: Limitations and Unrealized Advantages Of Using Reticular Pla...mentioning

confidence: 99%

Section: Limitations and Unrealized Advantages Of Using Reticular Pla...mentioning

confidence: 99%

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

Wijesundara,

Howlett,

Kumari

et al. 2024

Chem. Rev.

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“…Compared to other template materials, MOFs have been considered as ideal templates based on their high specific surface areas and high porosity . Particularly, zeolitic imidazolate framework (ZIF-8), composed of zinc ions and 2-methylimidazolate, exhibited excellent advantages as template material in nanoparticle fabrication due to the high loading capability, mild removal condition and pH-responsive dissociation. − Works from our lab and others showed that using ZIF-8 NPs as templates to prepare nanoparticles could achieve effective loading of payloads and intracellular delivery. − Additionally, poly(ethylene glycol) (PEG) could act as a mineralizer to improve the dispersity, stability, and cargo loading capacities of ZIF-8 NPs. − …”

Section: Introductionmentioning

confidence: 99%

Nanoengineering of Vaccine Nanoparticles via Templating of Metal–Organic Frameworks for Tumor Immunotherapy

Liu,

Wang,

et al. 2024

Chem. Mater.

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We present a facile strategy to fabricate nanovaccines through a metal−organic framework-templated method. The nanovaccines, named IMDQ@OVA-TA, were obtained through the interfacial assembly of model antigen ovalbumin (OVA) and tannic acid (TA) on imidazoquinoline (IMDQ)-encapsulated zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs). The coordination of Zn 2+ -imidazole, Zn 2+ -TA, and the molecular coassembly of TA with proteins resulted in the formation of stable nanovaccines under physiological conditions. The pH responsiveness granted to the nanovaccines by coordination bonds promotes IMDQ release at low pH values, antigen lysosomal escape, and cross-presentation. In C57BL/6 mice models, nanovaccines demonstrated long-term accumulation at the injection site, sustainable transportation to lymph nodes, and good therapeutic effects against E.G7-OVA lymphoma. Mechanism analysis revealed that the nanovaccines induced both innate and adaptive tumorspecific immune activation. Overall, our work presents a simple and general strategy for the fabrication of protein-polyphenol nanocapsules with toll-like receptor (TLR) 7/8 agonists for cancer immunotherapy.

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“…46 The presence of zinc in ZIF-8 has recently been shown to traffic to the lymph node and increase T-cell activation and cytokine production. 47 Further, Zn 2+ has implications in the activation of cGAS; Zn 2+ is necessary for the enzyme to produce the CDN cGAMP after the detection of DNA. 48 MOFs-the ZIF family in particular-can be tuned through reticular synthesis, allowing for the modular incorporation of multiple different linkers 49 or multiple metals 50 to create multivariate MOFs with properties unique or distinct from MOFs made of a single metal or ligand.…”

Section: Introductionmentioning

confidence: 99%

Mn and Zn-Doped Multivariate Metal-Organic Framework as a Metalloimmunological Adjuvant to Promote Protection Against Tuberculosis Infection

Howlett,

Kumari,

Ehrman

et al. 2024

Preprint

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A first-in-class vaccine adjuvant delivery system, Mn-ZIF, was developed by incorporating manganese (Mn) into the zinc-containing zeolitic-imidazolate framework-8 (ZIF-8). The mixed metal approach, which allowed for tunable Mn doping, was made possible by including a mild reducing agent into the reaction mixture. This approach allowed up to 50% Mn, with the remaining 50% Zn within the ZIF. This multivariate approach exhibited significantly decreased cytotoxicity compared to ZIF-8. The porous structure of Mn-ZIF enabled the co-delivery of the STING agonist cyclic di-adenosine monophosphate (CDA) through post-synthetic loading, forming CDA@Mn-ZIF. The composite demonstrated enhanced cellular uptake and synergistic activation of the cGAS-STING pathway, producing proinflammatory cytokines and activating antigen-presenting cells (APCs). In a preclinical Mycobacterium tuberculosis (Mtb) model, CDA@Mn-ZIF formulated with the CysVac2 fusion protein elicited a potent antigen-specific T-cell response and significantly reduced the mycobacterial burden in the lungs of infected mice. These findings highlight the potential of CDA@Mn-ZIF as a promising adjuvant for subunit vaccines, offering a novel approach to enhancing vaccine efficacy and protection against infectious diseases such as tuberculosis.

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A scalable synthesis of adjuvanting antigen depots based on metal–organic frameworks

Abstract: ZIF-8 vaccine enhances the humoral immune response through sustained antigen exposure to the immune system whilst zinc adjuvants the vaccine via inducing T cell activation.

Cited by 11 publications

References 69 publications

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

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

Nanoengineering of Vaccine Nanoparticles via Templating of Metal–Organic Frameworks for Tumor Immunotherapy

Mn and Zn-Doped Multivariate Metal-Organic Framework as a Metalloimmunological Adjuvant to Promote Protection Against Tuberculosis Infection

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