Modular protein-based delivery platforms for localized and/or targeted disease treatments

Abstract

Hydrogels and nanoparticles have been extensively explored as drug delivery platforms for both localized and systemic applications. Despite their therapeutic potential, their clinical translation is often hampered by limited biocompatibility and insufficient functional tunability. To address these limitations, protein-based materials have emerged as attractive alternatives, offering inherent biocompatibility, biodegradability, and modularity. These features make them highly suitable for the rational design of well-defined supramolecular assemblies tailored for biomedical applications. This thesis explores how rational protein design and assembly strategies can overcome the shortcomings of conventional drug delivery platforms. First, I developed self-crosslinkable protein hydrogels using two genetically engineered protein building blocks. This strategy enabled the formation of soft yet stable hydrogels without the need for chemical crosslinkers. The resulting injectable hydrogels provided a biocompatible platform for the localized and sustained release of therapeutic agents in cancer therapy and wound healing. Second, I engineered porous protein cage nanoparticles capable of efficient cargo loading within their internal cavities, while also allowing modular display of multiple targeting ligands on their external surfaces. These nanoparticles achieved effective targeted drug delivery, significantly reducing off-target cytotoxicity. Lastly, I established a targeted and safe toxin delivery system by integrating a cancer-specific toxin module with protein cage nanoparticles. This platform enabled selective tumor targeting and potent tumor suppression in vivo, with minimal off-target toxicity. Together, these studies demonstrate that rational protein engineering and modular assembly approaches can be harnessed to develop structurally precise and functionally tunable delivery platforms. Modular protein-based delivery platforms hold great potential for the advancement of versatile next-generation therapeutics for both localized and systemic drug delivery.