Cytokine Engineering Approaches for Regenerative Medicine

Abstract Cytokines are central in orchestrating immune responses during tissue repair and regeneration, making them attractive candidates for regenerative medicine. However, their pleiotropic effects, short half‐life, and poor biodistribution have limited their clinical translation. Advances in protein engineering have enabled the design of modified cytokines with enhanced stability, receptor selectivity, and tissue‐targeting capabilities, offering new therapeutic opportunities for modulating immune activity and promoting tissue healing. Many of these engineering approaches have been pioneered in cancer immunotherapy, where cytokines are often designed to sustain inflammation and enhance cytotoxic immune responses. In contrast, regenerative medicine usually requires immune resolution, necessitating a distinct and sometimes opposite application of cytokine engineering strategies. This review explores the latest advancements in cytokine engineering for regenerative applications, focusing on strategies to enhance cytokine stability, modulate receptor affinity, improve targeting, and regulate endogenous cytokine signaling. Numerous approaches, highlighting how targeted immune modulation can enhance tissue healing while minimizing fibrosis and chronic inflammation, are discussed. These advances hold great promise for treating chronic wounds, fibrotic diseases, and tissue injuries with limited regenerative capacity, paving the way for precise, effective, and clinically translatable cytokine therapeutics. By adapting principles from cancer immunotherapy, cytokine‐based therapies could transform regenerative medicine.