Cytokines have pivotal roles in immunity, making them attractive as therapeutics for a variety of immune-related disorders. However, the widespread clinical use of cytokines has been limited by their short blood half-lives and severe side effects caused by low specificity and unfavourable biodistribution. Innovations in bioengineering have aided in advancing our knowledge of cytokine biology and yielded new technologies for cytokine engineering. In this Review, we discuss how the development of bioanalytical methods, such as sequencing and high-resolution imaging combined with genetic techniques, have facilitated a better understanding of cytokine biology. We then present an overview of therapeutics arising from cytokine re-engineering, targeting and delivery, mRNA therapeutics and cell therapy. We also highlight the application of these strategies to adjust the immunological imbalance in different immune-mediated disorders, including cancer, infection and autoimmune diseases. Finally, we look ahead to the hurdles that must be overcome before cytokine therapeutics can live up to their full potential.

In the slipstream of targeting the adaptive immune system, innate immunotherapy strategies are being developed. In this context, technologies based on natural carrier vehicles that inherently interact with the innate immune system, are increasingly being considered. Immunoregulatory nanotherapeutics based on natural apolipoprotein A1 (apoA1) are discussed here. This protein is a helical, amphipathic macromolecule and the main constituent of high-density lipoprotein. In that capacity, apoA1 interacts specifically with innate immune cells, such as monocytes and macrophages, to collect and transport lipophilic molecules throughout the body. Exactly these unique features make apoA1 a compelling elementary constituent of biocompatible self-assembled nanotherapeutics. Such apoA1-based nanotherapeutics (A1-nanotherapeutics) can be engineered and functionalized to induce or mitigate an innate immune response or to orchestrate an adaptive immune response through antigen delivery to dendritic cells. The authors first discuss apoA1's properties and how these can be exploited to generate libraries of A1-nanotherapeutics using advanced manufacturing approaches such as microfluidics or continuous flow methods. Using high-throughput in vitro screening methods and in vivo imaging to identify promising formulations are then recommend. Finally, three distinct immunotherapy strategies are proposed to effectively treat a variety of diseases-including cancer, infection, and cardiovascular disease-and promote allograft survival in transplantation.

Immunoparalysis is a compensatory and persistent anti-inflammatory response to trauma, sepsis or another serious insult, which increases the risk of opportunistic infections, morbidity and mortality. Here, we show that in cultured primary human monocytes, interleukin-4 (IL4) inhibits acute inflammation, while simultaneously inducing a long-lasting innate immune memory named trained immunity. To take advantage of this paradoxical IL4 feature in vivo, we developed a fusion protein of apolipoprotein A1 (apoA1) and IL4, which integrates into a lipid nanoparticle. In mice and non-human primates, an intravenously injected apoA1-IL4-embedding nanoparticle targets myeloid-cell-rich haematopoietic organs, in particular, the spleen and bone marrow. We subsequently demonstrate that IL4 nanotherapy resolved immunoparalysis in mice with lipopolysaccharide-induced hyperinflammation, as well as in ex vivo human sepsis models and in experimental endotoxemia. Our findings support the translational development of nanoparticle formulations of apoA1-IL4 for the treatment of patients with sepsis at risk of immunoparalysis-induced complications.

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