Ferroptosis, a unique form of cell demise proposed by Dr. Brent R. Stockwell of Columbia University in 2012 [1], functions differently from other types of cell death, including apoptosis, necrosis, and autophagy. It is a programmed death process mediated by iron-dependent lipid peroxidation. Current investigations have revealed that ferroptosis primarily arises due to the peroxidation of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs) induced by reactive oxygen species (ROS) [2]. Ferroptosis displays promising potential for inhibiting tumor growth and overcoming drug resistance in cancer treatment [3]. Consequently, scientists have employed agents that induce ferroptosis (FINs) to augment its occurrence in cells. Nevertheless, these agents also result in inevitable toxicity to healthy cells, impeding their practicality. Hence, devising a safe strategy capable of selectively triggering ferroptosis in tumor cells represents an encouraging yet challenging approach to address the unmet need for effective chemotherapy suppression.

The tumor microenvironment, where tumor cells reside, is a complex network consisting of various immune cell types, cancer-associated fibroblasts, endothelial cells, pericytes, and other tissue-resident cell types [4]. Tumor-associated macrophages (TAM) comprise ∼30–50% of infiltrating cells around cancer cells and are immune cells capable of engulfing particles and releasing cytokines [5]. Inducing ferroptosis in cancer cells by disrupting the tumor microenvironment through macrophage polarization has been a focus of study [6]. Iron overload has been found to promote macrophage polarization towards the M1 phenotype through the ROS/acetyl-p53 pathway, characterized by increased pro-inflammatory cytokines and decreased M2 phenotype markers [7]. More importantly, M1-type TAMs tend to secret more H2O2, favoring the peroxidation of PUFA-containing phospholipids (PUFA-PLs) [8]. Moreover, TAMs also secret IFNγ, which has been reported to promote lipid peroxidation and ferroptosis by inhibiting SLC7A11 expression [9], [10]. Therefore, triggering macrophage M1 phenotype polarization through iron overload is an important therapeutic strategy for promoting ferroptosis.

Conventional chemotherapy effectiveness is often limited due to poor targeting and drug resistance [11], [12], [13], [14], [15]. Superparamagnetic iron oxide nanoparticles (SPIONs) have emerged as versatile nanoplatforms capable of magnetic-field guided targeted-delivering chemotherapeutic agents [16], [17], [18], [19], [20], [21], [22]. Recently, another characteristic of SPIONs, converting light to heat for photothermal conversion, has been extensively used for mild hyperthermia generation, controllable drug release, and iron supply [23], [24], [25]. Since SPIONs can supply an extracorporeal iron source to activate ferroptosis, the peroxidation of a great number of lipid molecules during ferroptosis inevitably affects drug efflux in tumor drug resistance [26]. Thus SPIONs are a promising candidate for serving as a ferroptosis-inducing nanoagent by synergizing chemotherapy, photothermal therapy, and ferroptosis therapy.

In this study, a multifunctional magnetic nanoparticle called rPAE@SPIONs was developed for enhanced tumor therapy. It is assembled using reducible poly(β-aminoester)-PEG amphiphilic copolymers and magnetic iron oxide nanoparticles. The unique hierarchical structure of rPAE@SPIONs enables the controlled release of DOX and iron ions, facilitating chemotherapy and ferroptosis therapy. Furthermore, it promotes iron overload-triggered macrophage polarization, enhancing chemotherapy by inducing ferroptosis of tumor cells. The photothermal conversion capability of rPAE@SPIONs further augments the therapeutic process (Scheme 1).