Engineering interleukin-10 for therapeutic applications

Interleukin-10 (IL-10) is a key immunoregulatory cytokine with potent anti-inflammatory and immunomodulatory functions. Its pleiotropic effects and short half-life, however, have posed challenges for direct therapeutic use. To overcome these hurdles, diverse engineering strategies have been developed to enhance IL-10 stability, tailor its activity, and target its delivery. This review describes the major approaches to IL-10 modification, including fusion proteins (e.g. cytokine/cytokine fusion, IL-10-Fc fusions for half-life extension, and bispecific constructs), encapsulation systems (nanoparticles and hydrogels for sustained or localized release), protein engineering of IL-10 monomers/dimers to modulate receptor engagement (decoupling pro- vs anti-inflammatory signaling), targeted delivery methods (antibody-mediated tissue targeting and intestinal-specific release), and receptor-based fusion proteins (immunoadhesins) to modulate IL-10 signaling. For each strategy, we highlight representative preclinical studies and clinical programs, examining pharmacodynamics, pharmacokinetics, efficacy in disease models (cancer, autoimmunity, colitis, fibrosis, transplantation), and translational potential. Advantages and limitations such as immunogenicity, delivery efficiency, and scalability are critically discussed. These advances collectively illustrate how bioengineering is unlocking IL-10 therapeutic potential while mitigating its prior limitations, paving the way for next-generation cytokine immunotherapies.