Sorafenib-Loaded Mesoporous Fe-Hematoporphyrin Complex for Ferroptosis-Enhanced Photodynamic Therapy of Colorectal...

Current colorectal cancer (CRC) therapies (e.g., surgery and radiotherapy) face challenges of invasiveness, drug resistance, and limited efficacy. Photodynamic therapy (PDT), a noninvasive modality, generates cytotoxic reactive oxygen species (ROS) via photosensitizers, offering a promising approach to overcome resistance. However, CRC and other solid tumors exhibit a hypoxic microenvironment with elevated glutathione (GSH) levels that scavenge ROS, severely compromising PDT efficacy. Developing advanced PDT systems to enhance ROS generation and overcome these microenvironmental barriers (e.g., hypoxia and GSH overexpression) is thus critical to improve CRC treatment outcomes and clinical translation. Herein, we report that a mesoporous Fe-hematoporphyrin complex (FeCP) was synthesized via covalent coordination of Fe³⁺ with hematoporphyrin. The FeCP exhibits a high surface area and tunable porosity, enabling efficient encapsulation of the ferroptosis inducer sorafenib (SOR) with a loading efficiency of 29.8%, as quantified by UV spectroscopy. Both in vitro and in vivo evaluations demonstrated that FeCP@SOR exhibited biocompatibility and synergistically enhanced photodynamic therapy (PDT) efficacy through dual redox modulation mechanisms. Mechanistically, FeCP@SOR significantly downregulated SLC7A11 expression, triggering substantial lipid peroxidation (LPO) and malondialdehyde (MDA) accumulation, as well as significant depletion of glutathione (GSH), ultimately inducing ferroptosis and alleviating tumor hypoxia. Concurrently, the amplified reactive oxygen species (ROS) generation disrupted intracellular redox homeostasis, intensifying tumor cell death and suppressing tumor growth. The FeCP@SOR nanocomposite demonstrated synergistic therapeutic effects against colorectal tumors, thereby offering a novel and reliable material platform for clinical photodynamic therapy (PDT) in colorectal cancer (CRC) management.