Modified biological hybrid nanoplatform for curcumin delivery and fe 3 ⁺ sensing to reverse CAF-derived QSOX1-mediated cisplatin resistance in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is characterized by poor therapeutic response and frequent chemoresistance, in which tumor microenvironment-mediated mechanisms play a critical role. Cancer-associated fibroblasts (CAFs) have been implicated in cisplatin resistance through the secretion of quiescin sulfhydryl oxidase 1 (QSOX1), which may contribute to the upregulation of multidrug resistance-associated genes such as ATP-binding cassette subfamily B member 1 (ABCB1, also known as P-glycoprotein, P-gp). In addition, dysregulated iron ion homeostasis within the tumor microenvironment highlights the need for multifunctional therapeutic strategies. Herein, a multifunctional nanoplatform (ALG-1-ATPMS@CP1@Cur) was developed to integrate targeted drug delivery with tumor microenvironment modulation. In vitro studies demonstrated that CAF-derived conditioned medium attenuated cisplatin-induced cytotoxicity in ESCC cells, whereas modulation of CAF signaling by Cur-loaded nanoparticles effectively restored drug sensitivity. Mechanistically, the nanoplatform significantly suppressed QSOX1 expression in CAFs and reduced ABCB1 expression in ESCC cells, suggesting a potential CAF–QSOX1–ABCB1 axis involved in chemoresistance. Furthermore, the nanoplatform exhibited pH-responsive drug release behavior and intrinsic Fe 3 ⁺ sensing capability, providing an auxiliary function for monitoring tumor microenvironment-related biochemical changes.