Bioorthogonal chemistry mediated cell engineering for advanced cell and cell-derived vesicle therapies: Principles, progresses, and remaining challenges

In the past few decades, cell and cell-derived vesicle therapies have experienced rapid development and played an increasingly important role in treating diverse diseases. Surface engineering can outfit cells and cell-derived vesicles with extrinsic functions to enhance efficacy. Nevertheless, traditional genetic, chemical, and physical cell engineering methods have limitations such as low efficiency, lack of specificity, and safety concerns, leading to a growing preference for bioorthogonal approaches. In light of its high efficiency, selectivity, and biocompatibility, bioorthogonal chemistry has been extensively employed in developing targeted or multifunctional delivery systems through direct bioorthogonal conjugation with target sites as well as coupling with nanoparticles, biomolecules, and chemotherapeutic drugs. In this review, we first introduced basic principles of bioorthogonal chemistry, including the main labeling pathways and typical bioorthogonal reactions. Then, we shed light on the recent breakthroughs in exploiting bioorthogonal chemistry to decorate multiple cells (stem cells, immune cells, cancer cells, islet β cells, and bacteria) and cell-derived vesicles for elevated target or combination therapy. Finally, we provide insights into the current limitations and future prospects of bioorthogonal chemistry in biomedical applications. This summary provides a panoramic view of bioorthogonal chemistry in cell and cell-derived vesicle therapies and inspires researchers to explore further applications of bioorthogonal chemistry in new indications.