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

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.

Hypoxia-activatable nano-prodrug for fluorescently tracking drug release in mice

Chemotherapy is one of the commonly used methods to treat various types of cancers in clinic by virtue of its high efficiency and universality. However, strong side effects and low concentration of conventional drugs at the tumor site have always been important factors that plague the chemotherapy effects of patients, further precluding their practical applications. Thereof, to solve the above dilemma, by integration of anticancer drug(nitrogen mustard, NM) into an NIR fluorophore(a dicyanoisophorone derivative), an intelligent prodrug NIR-NM was developed via molecular engineering strategy. Prodrug NIR-NM stimulated in hypoxia condition exhibits significantly higher toxicity to cancer cells than normal cells, essentially reducing the collateral damage to healthy cells and tissues of nitrogen mustard. More importantly, the nanoparticle prodrug FA-lip@NIR-NM showed the advantages of the high accumulation of drug at tumor site and long-circulation capacity in vivo, which endowed it the ability to track the release of the active chemotherapeutic drug and further treat solid tumors.