Reprogramming the glycocalyx: Advances in glycoengineering for immunomodulation and regenerative medicine

This review explores the evolving landscape of glycoengineering on the cell surface, a pivotal field in translational medicine with profound implications for immunomodulation and regenerative therapies. The cell membrane and glycocalyx, composed of proteins, lipids, and glycans, govern cellular interactions, immune recognition, and tissue regeneration. Given the dynamic nature and important biological roles of these structures, precise glycoengineering strategies are essential for modulating cell behavior without compromising function and safety. We delve into genetic and non-genetic approaches to manipulation of cell surface patterns, including targeted glycan and glycosaminoglycan modifications, metabolic glycoengineering, the use of synthetic glycopolymers, and bio-orthogonal glycan functionalization. Enzymatic strategies for glycan cleavage and addition further expand the toolkit for controlled cell surface remodeling. These advancements hold promise for cancer immunotherapy, organ transplantation, islet transplantation, and cardiovascular disease treatments. Despite the considerable potential of glycoengineering, a number of challenges, such as membrane instability and unintended cellular alterations remain, necessitating precise control over modifications. This review critically evaluates emerging strategies, discussing their limitations and future directions in biomedical and bioengineering applications. By integrating glycocalyx biology with advanced engineering techniques, we provide a roadmap for harnessing cell surface engineering to enhance therapeutic efficacy, immune modulation, biomaterial innovation, and regenerative medicine.