Tumor microenvironment-responsive DP-PEGylated manganese dioxide/methylene blue nanoparticle suspension for gastrointestinal labeling and dual-modality imaging

• Appropriate particle size (70–90 nm) with stable physicochemical properties, reproducible preparation, and strong clinical translation potential. • Precise visible marking with minimal diffusion and enhanced dual-modal T1/T2 MR imaging. • Visible retention ≥ 30 days and MR imaging ≥ 7 days, meeting perioperative requirements. • The method involves intraperitoneal injection rather than intravenous administration, clarifying the metabolic pathway and enhancing biosafety. Accurately determining the optimal surgical margin is essential for ensuring surgical accuracy and long-term prognosis. Existing localization approaches, including staining and localization, have limitations such as extensive halo effects, non-imaging and marker displacement. Thus, we designed a novel MB/(DP-PEG)-BSA@MnO 2 nanosuspension (MDPBMNs) , which demonstrates excellent biocompatibil- ity, with cell viability ≥ 75% across all concentrations. In vivo studies in SD rats and Bama minipigs revealed no abnormalities in survival status, histopathology, blood examination or oxidative stress indicators. MDPBMNs demonstrated outstanding parameters (83.70 ± 5.43 nm; PDI < 0.2), balanced surface charge and satisfactory stability. At 3.0 T, MDPBMNs can enhance dual-modal MR imaging capability, with relaxivity values of 1/T1 (12.3[Mn]mM −1 s −1 ) and 1/T2 (19.5[Mn]mM −1 s −1 ), corresponding to 3.65-fold and 4.63-fold higher than Gd-DTPA respectively. Following administration into the gastrointestinal serosa, the agent enabled precise visualization with distinct radiographic contrast and without observable halo diffusion. Mn 2+ was predominantly cleared through hepatic and renal pathways, alleviating concerns about organ deposition. Overall, MDPBMNs show enormous clinical translational potential for advancing precision surgery.