Oral route is one of the most important portals of nanoparticle entry to the body. However, in vivo protein corona formed in the gastrointestinal tract has not been studied owing...

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Nanomaterials have been widely applied in oral drug delivery. A number of indirect evidences suggest that nanoparticles can pass across gastrointestinal walls to enter the blood circulation system. However, there is still no direct evidence to prove that the intact nanoparticles can pass across gastrointestinal walls and the nanoparticles can retain their original structure after translocation across gastrointestinal walls. In the present study, the potential toxicity of dimercaptosuccinic acid coated Zn2+ doped magnetite nanoparticles (DMSA-Zn0.4Fe2.6O4) in the spleen, stomach, and small intestine of mice has been investigated after 30 days of repeated intragastric administration. We provide first direct evidence that intact DMSA-Zn0.4Fe2.6O4 can pass across the small intestinal barriers to enter blood circulation system and arrive in the spleen. In addition, our findings provide direct evidence that although the biotransformation of DMSA-Zn0.4Fe2.6O4 occurs in vivo, some DMSA-Zn0.4Fe2.6O4 retain their original structure after translocation across the small intestinal wall and deposition in the spleen. The results indicate the safety of DMSA-Zn0.4Fe2.6O4 in the applications in mice at a 50 mg/kg dose and highlight the unique advantage of DMSA-Zn0.4Fe2.6O4 in biomedical applications.