The human body functions as a natural reactor for a vast network of chemical and biological reactions and physical interactions among small molecules, proteins, cells, and numerous other components. These reactions/interactions are essential for maintaining normal physiological functions. From an engineering perspective, these molecular reactions and interactions can be exploited for disease diagnosis, therapeutic interventions, and a variety of biomedical applications. In this review, we summarize non-catalyzed molecular reactions and interactions that occur spontaneously under physiological conditions without enzymatic mediation. We discuss their biomedical implications in disease diagnosis, drug delivery, and biomaterials for regenerative and cellular engineering. Looking forward, we highlight emerging opportunities to leverage these spontaneous non-catalyzed reactions and interactions in drug design, nonenzymatic activation of genome editing in synthetic biology, and non-genetic surface modification and activation of immune cells.
Keywords: bioorthogonal ligation; boronate esterification; non‐catalyzed chemistry; schiff base formation; spontaneous reactions; thiol‐michael addition.
© 2026 The Author(s). Advanced Science published by Wiley‐VCH GmbH.