A CIA strategy with eminent drug-loading capacities for tumor ferroptosis-gas synergistic therapy

Rationale: A common challenge of drug loading and delivery using magnetic resonance imaging (MRI) contrast agents (CAs) is the tendency of aggregation and precipitation at high drug loading conditions. Herein, we propose a generic strategy of controlled ideal aggregation (CIA) to restrict the tendency. Methods: Fe²⁺, β-Lapachone (LAP), brequinar (BQR), or Sorafenib (SOR) was respectively loaded onto Gd poly (acrylic acid) macrochelate (GP), an MRI CA, in the hollow core of nitrite-modified hollow mesoporous organosilica nanoparticles (HMON-SNO). The aggregation of FeGP, LAPGP, BQRGP, and SORGP was controlled to be ideal without precipitation by the fixed space of the HMON-SNO hollow core. The sizes of the ideal aggregates are larger than the mesopore size of HMON-SNO, which prevents premature drug leakage and release. Results: After the accumulation of FeGP@HMON-SNO in tumors, the presence of glutathione (GSH) in the tumor microenvironment (TME) triggers the HMON-SNO degradation to release NO, Fe^2+, and GP. The released Fe²⁺ reacts with endogenous hydrogen peroxide (H₂O₂) to generate Fe³⁺ and hydroxyl radical (•OH). The -SNO groups on the surface of HMON-SNO react with GSH, enabling sustained NO generation. The elevated NO level induces mitochondrial dysfunction, down-regulates lipid droplets through the alleviation of hypoxia and consequently promotes the accumulation of lipid peroxidation (LPO) under excess •OH to induce tumor cell ferroptosis. Moreover, the released GP facilitates high contrast T ₁-weighted MRI of tumors due to its high r ₁ value, enabling real-time monitoring for the in vivo delivery of FeGP@HMON-SNO. Conclusions: The proposed strategy of CIA with universality was successfully utilized to restrict the aggregation of MRI CAs at high drug loading conditions. The developed FeGP@HMON-SNO with eminent drug loading content were used for tumor ferroptosis-gas synergistic therapy with high efficacy.