br injection The volumes of
injection. The volumes of tumors in the control groups dramatically increased at 8 days postinjection (Fig. 7C). However, Se, MCDION-1, MCDION-1+Se, and MCDION-Se presented diﬀerent degrees of tumor inhibition ability, and the inhibition eﬃciency was as follows: MCDION-1 < Se < MCDION-1+Se < MCDION-Se. Interestingly, unlike traditional chemotherapeutics [3,5], the tumor volumes of mice injected with MCDION-Se remained at a low level during the whole period of treatment and did not increase rapidly, which suggested that MCDION-Se could eﬀectively kill cancer tissue and avoid the generation of drug resistance. In addition, the photographs indicated that the MCDION-Se treatment showed a smaller tumor size than that of the other groups (Fig. 7F and Fig. S10), which was consistent with the above analysis results.
To obtain better clinical applications, it is necessary to assess the biodistribution, pharmacokinetic parameters, and side eﬀects of ther-anostic agents in vivo. As shown in Fig. 7D, mice treated with MCDION-Se showed a similar body weight change as those in the saline group, suggesting that MCDION-Se had no significant side eﬀect on the body. In addition, MCDION-Se quickly accumulated in the liver and spleen (Fig. 7E), which could be attributed to the existence of the re-ticuloendothelial system (RES) in the liver and spleen [44,45]. More-over, the accumulation of MCDION-Se in the kidney was low, sug-gesting that MCDION-Se was excreted from the body via the hepatic Conessine [46,47]. In addition, the content of MCDION-Se in the vital organs gradually decreased and reached a very low level on the 5th day postinjection, implying that this nanoplatform could not ac-cumulate in the long term and could avoid potential risks for vital or-gans. At the end of the cancer treatment, the Mn and Se contents of the tumors were analyzed using ICP-MS. The tumors in mice injected with MCDION-Se showed high Mn and Se contents compared with those in the other groups, indicating that MCDION-Se could be eﬀectively de-livered to the tumor tissue and that MCDION-Se had the best inhibitory eﬀect on tumors (Fig. S11).
The hematoxylin and eosin (H&E) staining analysis showed that the tumor biopsies of mice treated with saline had an abundance of ma-lignant hyperchromatic cancer cells (Fig. 7G). Nevertheless, the mice
treated with Se, MCDION-1, MCDION-1+Se, and MCDION-Se had dif-ferent degrees of tumor necrosis, and the necrotic area was in the order of Se < MCDION-1 < MCDION-1+Se < MCDION-Se, further sug-gesting that MCDION-Se had a strong therapeutic ability for tumors. In addition, tumors treated with MCDION-Se displayed more Caspase-3 proteins than those in the other groups, suggesting that many cancer cells were gradually dying (Fig. 7H). In addition, histological ex-amination of other vital organs showed that no significant damages appeared after treatment with MCDION-Se, MCDION-1+Se, MCDION-1, and Se, suggesting that MCDION-Se as a drug-free theranostic agent could significantly decrease the side eﬀect for body in comparison with traditional chemotherapeutics. These results indicated that our strategy utilizing a drug-free nanoplatform for tumor treatment has great pro-mise for clinical application.
In summary, a drug-free theranostic agent (MCDION-Se) was suc-cessfully developed and employed for real-time MRI and synergistic tumor treatment. This theranostic platform was synthesized via the integration of nano-Se and manganese carbonate-deposited ION and possessed multiple functions: CDT, limotherapy, and pH-responsive MR imaging for cancer. Mn2+ ions could be eﬀectively released from MCDION-Se in the tumor microenvironment, rendering MCDION-Se a precise diagnostic platform for tumor. In addition, MCDION-Se could be eﬀectively internalized by HeLa cells, dramatically enhancing the Fe, Mn, and Se contents in cancer cells. Subsequently, the loaded nano-Se could rapidly activate SOD and promote the generation of SOARs, which triggered a cascade reaction to form H2O2. Meanwhile, Mn2+ ions and ION further catalyzed the decomposition of H2O2 into highly toxic ·OH, which would cause the fast oxidation and deterioration of proteins and enhance the therapeutic eﬃciency of CDT. In addition, the Mn2+ ions and nano-Se in cancer cells also significantly limited the generation of ATP, thus starving the cancer cells. Therefore, this drug-free nanoplatform integrating MRI with synergistic eﬃcacy could be an excellent candidate for the development of the next generation of tumor