Because of the insufficiency of hydrogen peroxide, the relatively low rate of Fenton reaction, and the active glutathione (GSH) peroxidase 4 (GPX4) in tumor cells, it is difficult to achieve a desirable efficacy of ferroptosis therapy (FT) for tumors based on nanomaterials. Inspired by the concept of “cyclotron” in physics, in this study, a new concept of cycloacceleration of reactive oxygen species (ROS) generation in tumor cells to realize high‐performance FT of tumors is proposed. Typically, a magnetic resonance imaging (MRI) contrast agent of dotted core–shell Fe3O4/Gd2O3 hybrid nanoparticles (FGNPs) is prepared based on exceedingly small magnetic iron oxide nanoparticles (ES‐MIONs). Sorafenib (SFN) is loaded and poly(ethylene glycol) methyl ether‐poly(propylene sulfide)‐NH2 (mPEG‐PPS‐NH2) is grafted on the surface of FGNP to generate SA‐SFN‐FGNP via self‐assembly. The results of in vitro and in vivo demonstrate SA‐SFN‐FGNP can work with the acidic tumor microenvironment and endosomal conditions, Fenton reaction and system XC−, and generate cyclic reactions in tumor cells, resulting in specific cycloacceleration of ROS generation for high‐performance FT of tumors. The very high longitudinal relaxivity (r1, 33.43 mM−1 s−1, 3.0 T) makes sure that the SA‐SFN‐FGNP can be used for MRI‐guided FT of tumors.

To surmount the major concerns of commercial small molecule Gd chelates and reported Gd‐based contrast agents (GBCAs) for magnetic resonance imaging (MRI), a new concept of organogadolinium macrochelates (OGMCs) constructed from the coordination between Gd3+ and macromolecules is proposed. A library of macromolecules were screened for Gd3+ coordination, and two candidates [i.e., poly(acrylic acid) (PAA), and poly(aspartic acid) (PASP)] succeeded in OGMC formation. Under optimized synthesis conditions, both Gd‐PAA12 and Gd‐PASP11 OGMCs are outstanding T1‐weighted CAs owing to their super high r1 values (> 50 mm−1 s−1, 3.0 T) and ultralow r2/r1 ratios (< 1.6, 3.0 T). The ferromagnetism of OGMCs is completely different from the paramagnetism of commercial and reported GBCAs. The ferromagnetism is very weak (Ms < 1.0 emu g−1) leading to a low r2, which is preferred for T1 MRI. Gd3+ is not released from the OGMC Gd‐PAA12 and Gd‐PASP11, ensuring biosafety for in vivo applications. The safety and T1‐weighted MRI efficiencies of the OGMC Gd‐PAA12 and Gd‐PASP11 are tested in cells and mice. The synthesis method of the OGMCs is facile and easy to be scaled up. Consequently, the OGMC Gd‐PAA12 and Gd‐PASP11 are superior T1‐weighted CAs with promising translatability to replace the commercial Gd chelates.

A prevalent problem of magnetic resonance imaging (MRI) contrast agents (CAs) for drug loading applications is easy aggregation. The major concern of hollow mesoporous organosilica nanoparticles (HMONs) is hard control of untimely drug leakage. To overcome both problems, a new strategy of limited‐space controlled aggregation for generic enhancement of drug loading capability is proposed. Typically, MRI CAs of exceedingly small gadolinium oxide nanoparticle (GO) and Gd poly(acrylic acid) macrochelate (GP) are exploited to load doxorubicin (D) in HMONs hollow core. The GO@D@HMONs and GP@D@HMONs without precipitation formation display much higher drug loading contents (33.0 ± 4.9%, 39.6 ± 4.0%) than GO@D and GP@D with serious precipitation generation (4.7 ± 0.5% and 14.7 ± 3.4%), which can be ascribed to the generation of GO@D and GP@D aggregates with larger sizes in HMONs hollow core than the pore size of HMONs preventing the drug leakage. The tumor microenvironment (TME)‐specific glutathione (GSH)‐triggered degradation of HMONs and the controlled drug release behaviors reinforce the chemotherapeutic efficacy and alleviate side effects on normal cells/tissues. The GSH‐activatable T1‐MRI is favorable to high contrast tumor imaging. Overall, the strategy of limited‐space controlled aggregation is promising for generic enhancement of drug loading capability of MRI CAs, realizing MRI‐guided high‐performance cancer treatments.