Protein-responsive protein release of supramolecular/polymer hydrogel composite integrating enzyme activation systems

Hajime Shigemitsu,Tomonobu Matsuzaki,Itaru Hamachi,Saori Minami,Takuma Aoyama,Keisuke Nakamura,Ryou Kubota,Kenji Urayama

doi:10.1038/s41467-020-17698-0

Hajime Shigemitsu, Tomonobu Matsuzaki + Show 6 more

Open Access

https://doi.org/10.1038/s41467-020-17698-0

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Abstract

Non-enzymatic proteins including antibodies function as biomarkers and are used as biopharmaceuticals in several diseases. Protein-responsive soft materials capable of the controlled release of drugs and proteins have potential for use in next-generation diagnosis and therapies. Here, we describe a supramolecular/agarose hydrogel composite that can release a protein in response to a non-enzymatic protein. A non-enzymatic protein-responsive system is developed by hybridization of an enzyme-sensitive supramolecular hydrogel with a protein-triggered enzyme activation set. In situ imaging shows that the supramolecular/agarose hydrogel composite consists of orthogonal domains of supramolecular fibers and agarose, which play distinct roles in protein entrapment and mechanical stiffness, respectively. Integrating the enzyme activation set with the composite allows for controlled release of the embedded RNase in response to an antibody. Such composite hydrogels would be promising as a matrix embedded in a body, which can autonomously release biopharmaceuticals by sensing biomarker proteins.

Highlights

Non-enzymatic proteins including antibodies function as biomarkers and are used as biopharmaceuticals in several diseases
The enzyme-activity triggers (EATs) consists of the ligand of a target protein and an enzyme inhibitor, which are connected by a short linker
We used bovine carbonic anhydrase II as the enzyme, which has activity that is tentatively inhibited by EATs

Summary

Introduction

Non-enzymatic proteins including antibodies function as biomarkers and are used as biopharmaceuticals in several diseases. A non-enzymatic protein-responsive system is developed by hybridization of an enzyme-sensitive supramolecular hydrogel with a protein-triggered enzyme activation set. Several hydrogels have been demonstrated to respond to reactive stimuli, including redox reagents, light, and enzymes[13,14,15,16,17,18,19,20,21,22], it is still a challenge to rationally design hydrogels that respond to non-enzymatic proteins Such non-enzymatic protein-responsive hydrogels are expected to be useful for controlled release of biopharmaceuticals in response to disease-related biomarker proteins such as antibodies, secreted cytokines, and membrane receptors. We describe the development of non-enzymatic protein-responsive soft materials by integrating an enzyme-sensitive supramolecular hydrogel with a protein-triggered enzyme activation system (Fig. 1a). We succeed in the controlled release of the embedded RNase in response to an antibody from the composite hydrogel

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