Surface crosslinking of virus-like particles increases resistance to proteases, low pH, and mechanical stress for mucosal applications

Ahmed, Ali; Ganguillet, Suwannee; Turgay, Yagmur; Keys, Timothy G.; Causa, Erika; Fradique, Ricardo; Lutz‐Bueno, Viviane; Chesnov, Serge; Lin, Chien‐Ting; Lentsch, Verena; Kotar, Jurij; Cicuta, Pietro; Mezzenga, Raffaele; Slack, Emma; Radiom, Milad

doi:10.1101/2023.07.29.550271

Cited by 2 publications

(1 citation statement)

References 84 publications

(194 reference statements)

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“…The inherent immunogenicity of VLPs, while advantageous for vaccines, poses a significant challenge for drug delivery, as it can provoke immune responses leading to rapid clearance and possible side effects [12]. Addressing these issues involves incorporating pH-responsive modifications and proteaseresistant motifs to enhance stability [250][251][252][253], leveraging nanotechnology and surface modifications to augment targeting precision [254][255][256], and developing innovative strategies including "stealth" VLPs and biomimetic coatings to balance immunogenicity [257,258]. Such developments are pivotal in evolving VLPs into efficient, stable therapeutic delivery systems poised to yield enhanced clinical outcomes.…”

Section: Stability and Longevitymentioning

confidence: 99%

Translational Challenges and Prospective Solutions in the Implementation of Biomimetic Delivery Systems

Wang,

et al. 2023

Pharmaceutics

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Biomimetic delivery systems (BDSs), inspired by the intricate designs of biological systems, have emerged as a groundbreaking paradigm in nanomedicine, offering unparalleled advantages in therapeutic delivery. These systems, encompassing platforms such as liposomes, protein-based nanoparticles, extracellular vesicles, and polysaccharides, are lauded for their targeted delivery, minimized side effects, and enhanced therapeutic outcomes. However, the translation of BDSs from research settings to clinical applications is fraught with challenges, including reproducibility concerns, physiological stability, and rigorous efficacy and safety evaluations. Furthermore, the innovative nature of BDSs demands the reevaluation and evolution of existing regulatory and ethical frameworks. This review provides an overview of BDSs and delves into the multifaceted translational challenges and present emerging solutions, underscored by real-world case studies. Emphasizing the potential of BDSs to redefine healthcare, we advocate for sustained interdisciplinary collaboration and research. As our understanding of biological systems deepens, the future of BDSs in clinical translation appears promising, with a focus on personalized medicine and refined patient-specific delivery systems.

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Section: Stability and Longevitymentioning

confidence: 99%

Translational Challenges and Prospective Solutions in the Implementation of Biomimetic Delivery Systems

Wang,

et al. 2023

Pharmaceutics

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Surface Cross-Linking by Macromolecular Tethers Enhances Virus-like Particles’ Resilience to Mucosal Stress Factors

Ali,

Ganguillet,

Turgay

et al. 2024

ACS Nano

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Virus-like particles (VLPs) are emerging as nanoscaffolds in a variety of biomedical applications including delivery of vaccine antigens and cargo such as mRNA to mucosal surfaces. These soft, colloidal, and proteinaceous structures (capsids) are nevertheless susceptible to mucosal environmental stress factors. We cross-linked multiple capsid surface amino acid residues using homobifunctional polyethylene glycol tethers to improve the persistence and survival of the capsid to model mucosal stressors. Surface cross-linking enhanced the stability of VLPs assembled from Acinetobacter phage AP205 coat proteins in low pH (down to pH 4.0) and high protease concentration conditions (namely, in pig and mouse gastric fluids). Additionally, it increased the stiffness of VLPs under local mechanical indentation applied using an atomic force microscopy cantilever tip. Small angle X-ray scattering revealed an increase in capsid diameter after cross-linking and an increase in capsid shell thickness with the length of the PEG cross-linkers. Moreover, surface cross-linking had no effect on the VLPs' mucus translocation and accumulation on the epithelium of in vitro 3D human nasal epithelial tissues with mucociliary clearance. Finally, it did not compromise VLPs' function as vaccines in mouse subcutaneous vaccination models. Compared to PEGylation without cross-linking, the stiffness of surface cross-linked VLPs were higher for the same length of the PEG molecule, and also the lifetimes of surface crosslinked VLPs were longer in the gastric fluids. Surface cross-linking using macromolecular tethers, but not simple conjugation of these molecules, thus offers a viable means to enhance the resilience and survival of VLPs for mucosal applications.

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Surface crosslinking of virus-like particles increases resistance to proteases, low pH, and mechanical stress for mucosal applications

Cited by 2 publications

References 84 publications

Translational Challenges and Prospective Solutions in the Implementation of Biomimetic Delivery Systems

Translational Challenges and Prospective Solutions in the Implementation of Biomimetic Delivery Systems

Surface Cross-Linking by Macromolecular Tethers Enhances Virus-like Particles’ Resilience to Mucosal Stress Factors

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