Tumor–microenvironment activated programmable synergistic cancer therapy by bioresponsive rare-earth nanocomposite

Abstract Synergistic chemotherapy–photothermal therapy (CT–PTT) can improve the cancer treatment efficacy, but its treatment effect is still limited by factors such as targeting efficiency and treatment sequence. Herein, a H2S-responsive metal organic frameworks (MOFs) coated rare-earth nanocomposite (csEr@MOF) was constructed and loaded with a chemotherapeutic drug (DOX) and a heat shock protein (HSP) inhibitor (Shepherdin). As the drug-loaded csEr@MOF reaches the H2S-riched colorectal tumor region, based on the reaction between H2S and MOF, Shepherdin is released for inhibiting the function of HSPs, the generated CuS is used for PTT and DOX is released for CT. Monitoring by ratiometric imaging of rare-earth nanocomposite, it is possible to perform the precise treatment timing for PTT. With the help of Shepherdin, the treatment effect of PTT was enhanced. Therefore, programmable CT–PTT synergistic cancer therapy activated by a single H2S trigger is achieved in vitro and in vivo. This work provides new ideas for designing tumor microenvironment–responsive therapeutic agents for programmable synergistic therapy with better targeting and therapeutic efficiency.