Rational design of tumor-microenvironment (TME)-activated nanoformulation for precisely targeted cancer treatment has recently attracted an enormous attention. However, the all-in-one TME-activated theranostic nanosystems with a simple preparation and high biocompatibility are still rarely reported. Herein, catalase nanocrystals (CatCry) are first introduced as a tumor microenvironment activatable nanoplatform for selective theranostics of colon cancer. They are engaged as (i) a "nanoreactor" for silver nanoparticles (AgNP) synthesis, (ii) a nanovehicle for tumor delivery of anticancer drug doxorubicin (DOX), and (iii) an in situ O2 generator to relief tumor hypoxia. When CatCry-AgNP-DOX nanoformulation is within a tumor, the intratumoral H2S turns AgNP into Ag2S nanoparticles, inducing a photothermal effect and NIR-II emission under 808 nm laser irradiation and also triggering DOX release. Simultaneously, CatCry catalyzes intratumoral H2O2 into O2, relieving hypoxia and enhancing chemotherapy. In contrast, when delivered to healthy tissue without increased concentration of H2S, the developed nanoformulation remains in the "off" state and no theranostic action takes place. Studies with colon cancer cells in vitro and a murine colon cancer model in vivo demonstrated that CatCry-AgNP-DOX delivered a synergistic combination of PTT and enhanced chemotherapy, enabling complete eradication of tumor with minimal side effects. This work not only introduces nanoplatform for theranostics of H2S-rich tumors but also suggests a general strategy for protein-crystal-based nanomedicine.
Keywords: H2S activatable; NIR-II imaging; cancer chemotherapy; photothermal therapy; protein nanocrystals.