Programmable Singlet Oxygen Battery for Automated Photodynamic Therapy Enabled by Pyridone–Pyridine Tautomer Engineering

The efficacy of photodynamic therapy is hindered by the hypoxic environment in tumors and limited light penetration depth. The singlet oxygen battery (SOB) has emerged as a promising solution, enabling oxygen- and light-independent ¹O₂ release. However, conventional SOB systems typically exhibit an "always-ON" ¹O₂ release, leading to potential ¹O₂ leakage before and after treatment. This not only compromises therapeutic outcomes but also raises substantial biosafety concerns. In this work, we introduce a programmable singlet oxygen battery, engineered to address all the issues discussed above. The concept is illustrated through the development of a tumor-microenvironment-responsive pyridone-pyridine switch, PyAce, which exists in two tautomeric forms: PyAce-0 (pyridine) and PyAce (pyridone) with different ¹O₂ storage half-lives. In its native state, PyAce remains in the pyridone form, capable of storing ¹O₂ (t_1/2 = 18.5 h). Upon reaching the tumor microenvironment, PyAce is switched to the pyridine form, facilitating rapid and thorough ¹O₂ release (t_1/2 = 16 min), followed by quenched ¹O₂ release post-therapy. This mechanism ensures suppressed ¹O₂ production pre- and post-therapy with selective and rapid ¹O₂ release at the tumor site, maximizing therapeutic efficacy while minimizing side effects. The achieved "OFF-ON-OFF" ¹O₂ therapy showed high spatiotemporal selectivity and was independent of the oxygen supply and light illumination.