Stimuli-responsive theragnostic probes have emerged as powerful tools for integrated disease diagnosis and treatment. Among them, programable off–on–off systems represent a unique class of probes that undergo sequential activation and deactivation, enabling highly specific signal control and spatiotemporal precision. In this talk, we present the design and application of programmable theragnostic probes that are selectively activated by disease-associated biomarkers and subsequently deactivated upon therapeutic engagement or secondary stimuli. This reversible behaviour allows real-time monitoring of both pathological events and treatment progress. Building on this concept, we further developed a programmable singlet oxygen battery that enables deep-tissue disease treatment without relying on oxygen supply or light illumination, effectively overcoming the major limitations of traditional photodynamic therapy.