Research Article | Open Access

Volume 2023 |Article ID 0006 | https://doi.org/10.34133/bdr.0006

De Novo Design and Synthesis of Polypeptide Immunomodulators for Resetting Macrophage Polarization

Na Kong,^1,7 Hongru Ma,^2,3,7 Zhongji Pu,^2,3,7 Fengju Wan,^1,7 Dongfang Li,² Lei Huang,^2,3 Jiazhang Lian,^2,3 Xingxu Huang,^4,5 Shengjie Ling ,^1,6 Haoran Yu ,^2,3 Yuan Yao ^1,2,3

¹School of Physical Science and Technology, ShanghaiTech University,393 Middle Huaxia Road, Shanghai 201210, China
²ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311215, China
³College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, Zhejiang 310027, China
⁴Zhejiang Lab, Hangzhou, Zhejiang 311121, China
⁵School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
⁶Shanghai Clinical Research and Trial Center, Shanghai 201210, China
⁷These authors contributed equally to this work.

Abstract

Modulating the extracellular matrix microenvironment is critical for achieving the desired macrophage phenotype in immune investigations or tumor therapy. Combining de novo protein design and biosynthesis techniques, herein, we designed a biomimetic polypeptide self-assembled nano-immunomodulator to trigger the activation of a specific macrophage phenotype. It was intended to be made up of (GGSGGPGGGPASAAANSASRATSNSP)n, the RGD motif from collagen, and the IKVAV motif from laminin. The combination of these domains allows the biomimetic polypeptide to assemble into extracellular matrix-like nanofibrils, creating an extracellular matrix-like milieu for macrophages. Furthermore, changing the concentration further provides a facile route to fine-tune macrophage polarization, which enhances antitumor immune responses by precisely resetting tumor-associated macrophage immune responses into an M1-like phenotype, which is generally considered to be tumor-killing macrophages, primarily antitumor, and immune-promoting. Unlike metal or synthetic polymer-based nanoparticles, this polypeptide-based nanomaterial exhibits excellent biocompatibility, high efficacy, and precise tunability in immunomodulatory effectiveness. These encouraging findings motivate us to continue our research into cancer immunotherapy applications in the future.