Programmable Singlet Oxygen Battery for Automated Photodynamic Therapy Enabled by Pyridone-Pyridine Tautomer...

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.