In Vivo Membrane Engineering: An Approach to Remodeling Cell Interfaces

The cell membrane is a crucial interface that maintains cellular homeostasis and facilitates intercellular communication, playing a key role in regenerative medicine and immune regulation. To improve cell-targeting ability, immune evasion, therapeutic efficacy, and durability, membrane engineering has modified cells using physical, chemical, or biological techniques. Recent research on in vivo membrane engineering has highlighted approaches that avoid the complex steps of cell extraction and re-injection in cell therapy. Thus, by performing modifications directly within the physiological environment, this strategy preserves cellular activity and minimizes variability in in vivo adaptability, enabling more efficient cellular remodeling. This review systematically summarizes and forecasts the latest advances in in vivo membrane engineering strategies, including bioorthogonal chemistry, genetic engineering, in vivo membrane fusion, DNA nanotechnology, and trogocytosis. For each strategy, we discuss its underlying mechanisms, unique advantages, and current technical limitations. Furthermore, we evaluate the major challenges hindering clinical translation and propose potential directions for future research, aiming to provide a perspective for more precise, controllable, and safe cell therapy. STATEMENT OF SIGNIFICANCE: The cell membrane serves as a crucial interface for maintaining cellular homeostasis and facilitating intercellular communication, and thus plays a key role in regenerative medicine and immune regulation. In vivo membrane engineering enables direct cellular modification within physiological environments, avoiding cell extraction and reinfusion while preserving cellular activity and adaptability. This review summarizes recent advances in five in vivo membrane engineering strategies: bioorthogonal chemistry, genetic engineering, in vivo membrane fusion, DNA nanotechnology, and trogocytosis. Beyond summarizing recent advances, we compare their distinct strengths, limitations, and suitability for different biomedical applications, providing a framework for strategy selection. We further identify key challenges in targeting, controllability, and clinical translation. This review offers a perspective on developing more precise, controllable, and safe in vivo membrane engineering technologies.