Tumor-Microenvironment-Activated NIR-II Nanotheranostic Platform for Precise Diagnosis and Treatment of Colon Cancer

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.