利用合成生物学与蛋白拓扑工程发展新型智能水凝胶材料及其在蛋白药物光控释放中的应用

Recent years, development of controlled drug delivery system has become a new direction in the field of medicine. Photoresponsive hydrogel materials become more attractive due to its spatial and temporal controllability. However, the existing photoresponsive hydrogel materials are often composed of polysaccharides or chemical components, which are not ideal for protein-based drugs in aspects of loading capacity，biodegradability and maintaining the drug activity. In our previous work, we have developed multiple genetically encoded protein hydrogels. Their gelation processes were quite gentle and there was no toxicity of the degradation products. Herein, based on protein engineering and topology engineering, we believe that a novel protein hydrogel material could be synthesized through genetic programming, which could be applied to light-controlled targeted protein drug release. We propose employing four-arm structured SpyCatcher protein as precursors while incorporating CarH as the photoresponsive motif to develop photoresponsive protein hydrogels. Biofilm inhibitors, PslG and PodA, will be constructed and integrated into the protein hydrogel network. Drug-loading and sustained-release properties of the photoresponsive protein hydrogels will be evaluated in mouse implant models. This study provides a novel universal strategy for controlled release of protein drugs in vivo, and opens up new opportunity for the treatment of diseases which may need remote control of drug release.

近年来，开发可控的生物大分子药物缓释体系成为了医药学领域新的发展方向。光控水凝胶体系因其时空精度的可控性受到广泛关注。但是目前已有的光控缓释体系一般为多糖或化学成分的水凝胶，在维持蛋白质药物活性、载药容量及降解物安全性上不太理想。前期我们已通过合成生物学的方法，构建出多种性能各异的蛋白质水凝胶材料，成胶过程温和，可生物降解，无毒无害。我们认为可通过适当的基因改造，结合蛋白质拓扑工程的方法，合成出新型的性能更加优越且对光响应的蛋白质水凝胶材料，应用于靶向蛋白质药物光控释放。本项目拟通过生物合成出四臂结构的SpyCatcher蛋白质作为反应前体，结合光响应基元CarH蛋白，开发可对绿光响应的水凝胶材料，并整合生物膜抑制蛋白PslG和PodA来检验该光控蛋白质水凝胶在小鼠植入物感染模型中的缓释性能。该研究提供了一个在体内进行高效蛋白质药物可控释放的普适性方法，为远程疾病治疗提供了新的思路。

近年来，开发可控的生物大分子药物缓释体系成为了医药学领域新的发展方向。光控水凝.胶体系因其时空精度的可控性受到广泛关注。但是目前已有的光控缓释体系一般为多糖或化学.成分的水凝胶，在维持蛋白质药物活性、载药容量及降解物安全性上不太理想。前期我们已通.过合成生物学的方法，构建出多种性能各异的蛋白质水凝胶材料，成胶过程温和，可生物降解.，无毒无害。我们认为可通过适当的基因改造，结合蛋白质拓扑工程的方法，合成出新型的性.能更加优越且对光响应的蛋白质水凝胶材料，应用于靶向蛋白质药物光控释放。本项目拟通过.生物合成出四臂结构的SpyCatcher蛋白质作为反应前体，结合光响应基元CarH蛋白，开发可对.绿光响应的水凝胶材料，并整合生物膜抑制蛋白PslG和PodA来检验该光控蛋白质水凝胶在小鼠.植入物感染模型中的缓释性能。该研究提供了一个在体内进行高效蛋白质药物可控释放的普适.性方法，为远程疾病治疗提供了新的思路。