Personalised and precision medicines are emerging as the future of therapeutic strategies. Biochemically triggered cleavable conjugation is thus crucial and timely due to its potential to response as per the loco-regional environment. It enables targeted release of therapeutic agents in response to specific biochemical signals and thus minimizing off-target effects and improving treatment precision. It holds promise in a range of biomedical applications, including cancer therapy, senolytic therapy, gene therapy, and regenerative medicine. The focus of this review is to offer comprehensive insight into the significance of biochemically cleavable conjugations within intrinsically stimuli-responsive architectures. Pathological conditions and alteration in tissues microenvironment in the body exhibit distinct biochemical settings characterized by change in redox potential, pH level, hypoxia, reactive oxygen species (ROS), and various catalytic protein/enzyme overexpression. Understanding these intrinsic features is crucial for researchers aiming to develop intelligent cleavable bio-engineered systems for biomedicines. By strategically designing cleavable linkage, researchers can leverage the variations in the tumor, infection, inflammation, and senescence microenvironments. Through an extensive examination of relevant literature, we present a comprehensive classification of the intrinsic physicochemical differences found in pathological areas and their applications in drug delivery, prodrug activation, imaging, and theranostics for future personalised medicines. This review will provide comprehensive guidance and critical insights to researchers in both industry and academia who are involved in the design of advanced, functional biochemically cleavable conjugations.
