"Dual-lock"-controlled activatable nanotheranostics for chemiluminescence resonance energy transfer (CRET)-driven...

Photoimmunotherapy is a promising therapeutic modality which utilizes phototherapy to trigger immune responses for cancer therapy. However, the requirement of light to trigger the therapeutic procedure greatly suppresses its efficacy against deep-seated tumors because of the low tissue penetration of light. To overcome this bottleneck, we herein construct a unique hydrogen sulfide/hydrogen peroxide (H₂S/H₂O₂) "dual-lock"-controlled activatable nanotheranostic system (RCblC@ZTP) that enables chemiluminescence resonance energy transfer (CRET)-driven exogenous light-free photoimmunotherapy. This "dual-lock" design requires the simultaneous presence of two tumor-specific stimuli to activate the therapeutic function of RCblC@ZTP, realizing precise and controllable tumor treatment. RCblC@ZTP is prepared by encapsulating bis[2,4,5-trichloro-6-(pentyl-oxycarbonyl)phenyl]oxalate (CPPO) and a hypoxia-responsive prodrug RCbl with an amphiphilic copolymer ZTP, which is composed of zinc-tetraphenylporphyrin (ZnTPP), copper bipyridine and polyethylene glycol (PEG). The photodynamic efficacy of RCblC@ZTP is quenched by copper bipyridine under physiological conditions. In contrast, the overexpressed H₂S in colorectal cancer can react with copper ions to form CuS and eliminate the quenching effect. After that, tumor overexpressed H₂O₂ reacts with CPPO to generate the intermediate 1,2-dioxetanedione, which further transfers the energy into ZnTPP via CRET. The excited ZnTPP can generate singlet oxygen (¹O₂). On the other hand, RCbl can release R848 and N¹,N¹-bis(2-chloroethyl)benzene-1,4-diamine (Cbl) under hypoxia. The generated ¹O₂ and Cbl can induce cancer cell apoptosis and trigger immunogenic cell death (ICD), while R848 can help the maturation of dendritic cells (DCs). The activated immune responses can not only kill primary tumors, but also inhibit liver and lung metastasis. Thus, our study reports a H₂S/H₂O₂ "dual-lock"-controlled nanosystem for activated photoimmunotherapy without exogenous light excitation.