A powerful bioorthogonal toolbox boosting the development of immune theranostics

Bioorthogonal chemistry encompasses a series of rapid and selective reactions that proceed under physiological conditions without interfering with essential biological functions. Over the past few decades, benefiting from its simplicity and efficiency, bioorthogonal chemistry has provided non-chemists with a powerful toolbox to advance chemical biology research and develop innovative biomedical strategies, leading to significant breakthroughs in disease treatment. With a growing understanding of pathological biology and immunology, immune theranostics has emerged as a next-generation strategy for precise disease diagnosis and treatment, as exemplified by the clinical success of CAR-T cell therapy. Indeed, prevalent advances have demonstrated that bioorthogonal chemistry significantly facilitates the construction of immune theranostic platforms. Recognizing its growing importance, this review provides an overview of the ideal bioorthogonal reactions suitable for biomedical applications. Additionally, we systematically summarize promising bioorthogonal-enabled applications for the ex vivo construction of immunotherapeutic agents (e.g. antibody–drug conjugates, vaccines, engineered cells, etc.). Furthermore, we also highlight recent developments in in vivo immunomodulation and precision diagnostics via bioorthogonal chemistry. Finally, we discuss the existing challenges and limitations associated with bioorthogonally driven immune theranostics, aiming to inspire future research toward enhancing its practical performance and clinical translation.