A transferrin-targeted nanoplatform for MRI-guided visualization and potent suppression of tumors and pulmonary metastatic lesions

While targeted theranostics for cancer remains a pivotal research frontier, conventional ligand conjugation strategies exhibit persistent limitations in off-target accumulation and suboptimal tumor specificity, ultimately failing to achieve reliable detection of early-stage lesions or metastatic nodules while demonstrating insufficient therapeutic payload delivery. In this study, the manganese sulfide (MnS) nanoplatform was synthesized using transferrin (Tf) with tumor-targeting properties as a carrier by a simple fabrication method. Notably, compared to clinically prevalent Gd-based contrast agents, Tf-MnS exhibited superior <i>T</i>₁-weighted magnetic resonance imaging (MRI) contrast performance, with the longitudinal relaxation (<i>r</i>₁) reaching 7.5253 mM^-1 s^-1, which was significantly higher than 3.2915 mM^-1 s^-1 of Gd-DTPA, and in the MRI of subcutaneous tumors and lung metastatic lesions in mice, the maximum relative signal-to-noise ratios reached 46.33% and 40.33%, respectively. Remarkably, upon reaching the acidic tumor microenvironment, Tf-MnS disintegrated to release Mn²⁺ ions and hydrogen sulfide (H₂S). The Mn²⁺ ions participated in Fenton-like reactions to produce cytotoxic hydroxyl radicals, while H₂S concurrently inhibited catalase enzyme activity, thereby alleviating the insufficiency of the hydrogen peroxide substrate and amplifying the therapeutic outcome. This synergistic mechanism endowed Tf-MnS with a self-enhanced anti-tumor effect, inhibiting both lung metastatic lesions and subcutaneous tumors in mice of the Tf-MnS group, with a tumor inhibition rate of 54.26%. Collectively, this work proposes an innovative strategy for integrating accurate diagnosis and self-augmented therapy of tumors and lung metastatic lesions into a unified nanoplatform, offering a promising methodology for precision oncology.