A Sterically Controlled and Tumor-Activated Programmable Singlet-Oxygen Battery

Limited light penetration and insufficient oxygen supply within the tumor microenvironment have been the "Achilles' heel" of traditional photodynamic therapy. Programmable singlet-oxygen batteries (PSOBs) have emerged as a promising strategy to overcome these challenges, capable of storing ¹O₂ pretherapy and releasing it during therapy in the tumor microenvironment, independent of light and oxygen supply. However, effective strategies for constructing lifetime tunable PSOBs remain limited, thereby limiting their application in different scenarios. Herein, we introduce a sterically controlled PSOB strategy featuring an "OFF-ON-OFF" controlled release of ¹O₂ at a tumor site. Specifically, linear substitutions at the bridgehead carbon of SOB-A and SOB-B enhance ¹O₂ storage stability with <i>t</i>_1/2 values of 10.5 and 8.7 h, respectively. SOB-A and SOB-B can be further stabilized by a nanoconfinement effect when encapsulated in Cu (II)-based MOF-199 with a significantly increased half-life of approximately 60 h, ensuring low side-effect pretherapy. On the other hand, in the tumor microenvironment, MOF-199 serves as a precursor of Cu(I), catalyzing the in situ synthesis of SOB-AB with larger cyclic steric hindrance, rapidly releasing ¹O₂ with a <i>t</i>_1/2 of 9.5 min during therapy. This approach unveiled the impact of surrounding steric hindrance on the stability of a metastable oxygen bridge in PSOBs. This paves the way for the next generation of PSOB by constructing dynamic steric effects in the bridgehead carbon, maximizing its efficiency for ¹O₂ delivery with minimized side effects.