FAPI-engineered nanoprobe induces dual-cell ferroptosis therapy and enables light-up magnetic resonance imaging for gastric cancer peritoneal metastasis

Gastric cancer with peritoneal metastasis (GC PM) is associated with poor prognosis and limited therapeutic options. Cancer-associated fibroblasts (CAFs), as critical components of the tumor microenvironment (TME), drive tumor progression and confer treatment resistance. Single-cell RNA-seq analysis of gastric cancer specimens revealed that GPX4 expression was elevated in CAFs, indicating their intrinsic resistance to ferroptosis. To overcome this stromal barrier, we developed a multifunctional theranostic nanoprobe, integrating ferroptosis induction, CAF-targeted delivery, and magnetic resonance imaging (MRI). The nanoprobe co-delivers cisplatin (CDDP) and mesoporous superparamagnetic iron oxide nanoparticles (MSPIONs) to enhance lipid peroxidation and is further modified with fibroblast activation protein inhibitor (FAPI) to achieve selective accumulation in CAFs. A pH-responsive gadolinium-based contrast agent Gd-PASP (GP) allows <i>T</i> ₂-to-<i>T</i> ₁ signal conversion, generating a distinct light-up effect under MRI. After integrating all these components, the final formulation is referred to as CDDP2@MSPION@GP3/FAPI. <i>In vivo</i> evaluations in CAF-enriched subcutaneous and peritoneal metastasis models confirmed efficient CAF targeting, dual-cell ferroptosis activation, stromal disruption, tumor inhibition, and enhanced imaging contrast. This study presents a smart, integrated strategy for ferroptosis-based nanotheranostics, offering a precise and effective approach to treating GC PM.