Multifunctional drug delivery of nanofibrous iron-polyphenolic nanochelates improved photothermal therapy against colorectal cancer via ferroptosis

Ferroptosis is a novel anticancer therapeutic approach that effectively circumvents the apoptotic cell death mechanism. Nonetheless, enhancing the catalytic effectiveness of the Fe²⁺-mediated Fenton reaction and effectively inducing ferroptosis present significant challenges. In this study, motivated by the kinetics of hyperthermia-improved Fenton reactions, we initially developed Quercetin (QT)-Curcumin (CUR)-Iron (Fe)-coordinated nanochelates for photothermal-improved ferroptosis in anticancer therapy. We precisely adjusted the appropriate feeding rate of polyvinylpyrrolidone (PVP), QT, CUR, and Fe to develop unique nanofibrous QT-CUR-Fe chelates, referred to as QCFs. The differences in size and structure made QCFs more practical for colorectal cancer therapy than ultrasmall QT-Fe (QFs). Under NIR laser exposure, QCFs can continuously enhance the formation of depleted excessive GSH and toxic hydroxyl radicals (•OH), leading to increased lipid peroxidation (LPO) accumulation and subsequently activating the ferroptosis pathway in vitro. Furthermore, the incorporation of CUR may suppress prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) in conjunction with PTT-improved ferroptosis colorectal therapy to facilitate dendritic cell (DC) maturation, elicit immunogenic cell death (ICD), and enhance synergistic antitumor immunotherapy. Overall, this study proposed a way to integrate small-molecule immunomodulators into QFs nanocoordination to overcome its limitations, thereby fostering a novel design concept for colorectal cancer therapy.