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

<b>Rationale</b>: 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. <b>Methods</b>: 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. <b>Results</b>: 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 (<b>•</b>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 <b>•</b>OH to induce tumor cell ferroptosis. Moreover, the released GP facilitates high contrast <i>T</i> ₁-weighted MRI of tumors due to its high <i>r</i> ₁ value, enabling real-time monitoring for the <i>in vivo</i> delivery of FeGP@HMON-SNO. <b>Conclusions</b>: 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.