Programmable Singlet Oxygen Battery for Automated Photodynamic Therapy Enabled by Pyridone–Pyridine Tautomer Engineering
Jianwu Tian, Bowen Li, Chongzhi Wu, Zhiyao Li, Honglin Tang, Wentao Song, Guobin Qi, Yufu Tang, Ping Yuan, Bin Liu
Abstract
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 1 O 2 release. However, conventional SOB systems typically exhibit an “always-ON” 1 O 2 release, leading to potential 1 O 2 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 1 O 2 storage half-lives. In its native state, PyAce remains in the pyridone form, capable of storing 1 O 2 ( t 1/2 = 18.5 h). Upon reaching the tumor microenvironment, PyAce is switched to the pyridine form, facilitating rapid and thorough 1 O 2 release ( t 1/2 = 16 min), followed by quenched 1 O 2 release post-therapy. This mechanism ensures suppressed 1 O 2 production pre- and post-therapy with selective and rapid 1 O 2 release at the tumor site, maximizing therapeutic efficacy while minimizing side effects. The achieved “OFF–ON–OFF” 1 O 2 therapy showed high spatiotemporal selectivity and was independent of the oxygen supply and light illumination.