Chemiluminescence-Powered DASA Photoswitching Enables Tumor-Activated Drug Release

Light-dependent drug delivery systems (LDDSs) are fundamentally constrained by limited tissue penetration of external irradiation. Here we report a chemically powered nanoplatform (CPC-nano) that eliminates the need for external light by coupling chemiluminescence (CL) with photoswitchable donor–acceptor Stenhouse adducts (DASAs). A DASA-PEG amphiphile was engineered to undergo hydrophobic-to-hydrophilic isomerization upon optical excitation. By coencapsulating a peroxalate CL substrate (CPPO) and an aggregation-enhanced fluorescent emitter (BLSA), endogenous H 2 O 2 is converted into sustained green CL via a chemically initiated electron-exchange luminescence (CIEEL) process. Favorable energetic matching and strong spectral overlap enable efficient CL-driven excitation of DASA, triggering micellar disassembly and rapid doxorubicin release. CPC-nano exhibits H 2 O 2 -specific activation, enhanced intracellular drug release with pronounced nuclear accumulation, and deep penetration in multicellular tumor spheroids. This work establishes a general strategy for integrating CL with photoswitchable materials, providing a self-powered, spatially confined approach to overcome light-penetration limitations in stimulus-responsive drug delivery.