The first biological element that materials, including biomolecules and exogenous/artificial factors, contact with is the cell membrane. The interface between the materials and the cell membrane is the first gateway for the materials. It is the place for a living organism to decide the fate of materials：to be “rejected,”“avoided,” or “tolerated.” This review will introduce high-speed live-cell atomic force microscopy to observe the material-cell membrane interface and fluorescence bioimaging to visualize cellular responses against the materials. Prospects for their correlative imaging will also be discussed. These technologies must provide a better understanding of how the strength of material-cell membrane interaction is decoded and how it determines the fate of cell and materials. In other words, they might be the basis to realize weak and specific interaction and the material symbiosis.

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Immunoreceptors play an important role in maintaining homeostasis in the body by distinguishing between self and non-self, and by acting as a starting point for immune activation and inhibition signals. However, unlike soluble proteins such as antibodies, the binding affinity between immunoreceptors and their ligands is weak and especially, the dissociation is rapid, making accurate assessment of binding affinity difficult. In this review, we focused on this weak and fast interactions in ligand recognition by immunoreceptors and introduce kinetic, thermodynamic, and structural aspects of molecular recognition mechanisms using physicochemical and structural methods.

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Poly（ethylene glycol）s（PEGs） have been the most widely used polymer, and PEGylation onto proteins, as well as nanoparticles has become a gold standard technique. PEGs have a long history of safe use in humans, however, induction of anti-PEG antibodies was observed in not only patients, who received PEGylated therapeutics, but also healthy subjects. As many more PEGylated therapeutics have been examined in clinical trials, a better understanding of PEG-related interactions, as well as responses is crucial for development of not only PEGylated therapeutics, but also materials in biomedical fields. The current review summarizes PEG-related specific interactions. Two step interactions are suggested to understand why PEG-conjugates exhibit irreversible bindings, whereas PEGs exhibit only rapid/weak interactions. The current review uncovers PEG-related interactions, and understanding of roles of PEGs will be beneficial for further development of biopharmaceutics.

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In recent years, nucleic acid drugs have gained a great deal of attention as a new drug discovery platform. With sophisticated artificial nucleic acid technology, issues such as 1） target affinity and selectivity, 2） in vivo stability, and 3） side effects such as immune response have been overcome one by one, and the expansion of indications is being vigorously pursued. On the other hand, even highly optimized nucleic acid drugs are still associated with side effects and have yet to be widely used. In this paper, we will discuss some known physicochemical interactions between nucleic acid drugs and living organisms to find clues for the development of more effective and safer nucleic acid drugs, which we refer to as “For realizing Material Symbiosis with nucleic acid drugs.”

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Allergies and autoimmune diseases caused by the breakdown of immune tolerance to harmless foreign antigens and self-antigens have been attracting attention in recent years as the number of patients increases. The development of antigen-specific immunotherapy for complete cure of allergies and autoimmune diseases, which artificially induces immune tolerance to antigens, has been studied. Immune tolerance therapy requires efficient and specific delivery of antigens to target immune cells, followed by induction of immune cells into a tolerogenic phenotype or anergy. In this process, drugs are required to perform three functions：evasion of the immune response to the antigen, targeting of the immune cells, and regulation of the immune cells. In this review, strategies and drug design for inducing antigen-specific immune tolerance are outlined, examples of recent research are presented, and future prospects are discussed.

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The field of biomaterials has seen a strong rejuvenation due to the new potential to modulate immune system in our body. This special class of materials is called “immunomodulatory biomaterials”. Generally, three fundamental strategies are followed in the design of immunomodulatory biomaterials：（1）immuno-inert biomaterials, （2）immuno-activating biomaterials, and （3）immuno-tolerant biomaterials. While many applications of immuno-inert biomaterials such as biocompatible medical implants have been already proposed in the past decades, the ability to engineer biological activity into synthetic materials greatly increases the number of their potential uses and improves their performance in more traditional applications. The major focus of researchers is now set on developing immuno-tolerant biomaterials for anti-inflammatory therapies. In this review, we therefore introduce recent developments of immuno-tolerant biomaterials. Especially we introduce an apoptotic cell membrane inspired polymer and its post-inflammatory effects on immune cells in this article.

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The intestinal mucosa is constantly exposed to foreign substances and thus owns several lines of defense machinery, including epithelial barrier and secretory IgA to prevent the invasion of pathogens. Meanwhile, the intestinal immune system elicits immune tolerance to food antigens and commensal bacteria. Dysregulation of the intestinal immunity often causes severe inflammatory disorders such as inflammatory bowel disease, allergies, and autoimmune diseases. Regulatory T（Treg） cells, one of the major T cell subsets in the intestine, play a critical role in maintaining immune homeostasis. Compelling evidence has demonstrated that commensal bacteria in the intestine are essential for the expansion of Treg cells in the intestinal lamina propria. This effect is at least partly mediated by metabolites like butyrate produced by commensal bacteria. Bacterial metabolites are transported to the bloodstream to affect the immune response in local and systemic tissues, especially in the respiratory system. Thus, the regulation of immune response by gut microbiota and its pathological relevance has drawn much attention. Furthermore, the development of therapies targeting the gut microbiota by fecal transplantation and probiotic administration is underway. This article will review the latest findings on the immune regulation by commensal bacteria and discuss therapeutic intervention strategies targeting the intestinal microbiota.

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Oral semaglutide tablets（Rybelsus^Ⓡ） is the world’s first once-daily oral formulation for glucagon like peptide-1（GLP-1） receptor agonist approved with the indication of type 2 diabetes mellitus in June 2020 in Japan. Oral semaglutide is co-formulated with the absorption enhancer salcaprozate sodium （SNAC） which enable to the oral absorption of semaglutide with high molecular weight peptide. This drug can be expected to improve adherence in the treatment by anti-diabetic drugs, as it is considered lower risk of hypoglycemia due to the glucose-dependent blood sugar lowering effect. This article describes the oral absorption enhancement mechanism of semaglutide by SNAC, pharmacokinetics and clinical trial results of oral semaglutide.

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