Enzyme-instructed hybrid nanogel/nanofiber oligopeptide hydrogel for localized protein delivery

Abstract

Enzyme-catalysis self-assembled oligopeptide hydrogel holds great interest in drug delivery, which has merits of biocompatibility, biodegradability and mild gelation conditions. However, its application for protein delivery is greatly limited by inevitable degradation of enzyme on the encapsulated proteins leading to loss of protein activity. Moreover, for the intracellularly acted proteins, cell membrane as a primary barrier hinders the transmembrane delivery of proteins. The internalized proteins also suffer from acidic and enzymatic degradation in endosomes and lysosomes. We herein develop a protease-manipulated hybrid nanogel/nanofiber hydrogel for localized delivery of intracellularly acted proteins. The embedded polymeric nanogels (CytoC/aNGs) preserve activity of cytochrome c (CytoC) that is an intracellular activator for cell apoptosis as a model protein against proteolysis, and do not affect the gelation properties of the protease-catalysis assembled hydrogels. The injectable hydrogel (CytoC/aNGs/Gel) serves as a reservoir to enhance intratumoral retention and realize sustainable release of CytoC/aNGs. The released CytoC/aNGs increase cellular uptake of CytoC and enhance its intracellular delivery to its target site, cytoplasm, resulting in favorable apoptosis-inducing and cytotoxic effects. We show that a single local administration of CytoC/aNGs/Gel efficiently inhibit the tumor growth in the breast tumor mouse model.

Hybrid Systems of Nanofibers and Polymeric Nanoparticles for Biological Application and Delivery Systems

“…Hydrogels with a porous structure that allow a large volume of water have also been reported, which provide a more favorable environment to encapsulate biological products such as cells and proteins [ 94 ]. The composite systems also provide protection against degradation [ 95 ].…”

Smart drug delivery systems for precise cancer therapy

“…Specifically, a structurally diverse hydrogel library with more than 2000 motifs 239 can link the chemical features of carriers with their self-assembly properties and accurately predict the gel formation ability by deep learning. Hydrogels offer scalable and tunable delivery platforms which can load a variety of drugs by hydrophobic domains, affinity-mediated binding, or covalent integration 240 , 241 . These kinds of design and prediction tools represent a future direction of the smart anticancer NDDS.…”

Development of a Polysaccharide-Based Hydrogel Drug Delivery System (DDS): An Update

“…Proteins and peptides show promising therapeutic potential; however, they often present limitations such as low stability, low bioavailability, and high immunogenicity [80][81][82]. Some of these issues can be solved by using hydrogels as the DDS.…”

“…An embedded polymeric nanogel was found to preserve the activity of cytochrome c, an activator of cell apoptosis. The nanogels (CytoC/aNGs) increased the cellular uptake of cytochrome c and improved the intracellular delivery to the targeted sites to induce apoptosis [82]. In another study, pH and glucose dual-responsive biodegradable nanogels were constructed and showed the release of the encapsulated proteins [83].…”