Cancer constitutes a grave menace to human well-being and inflicts a colossal economic burden on global society [1]. In recent years, novel cancer treatment modalities and anti-neoplastic agents exhibit tremendous potential to revolutionize the landscape of cancer therapy. Ferroptosis is a new strain of programmed cell death resulting from an imbalance between the production and elimination of lipid peroxidation [2], [3]. It is a tumor suppressor that exerts a pivotal function in eliminating cancer cells and curbing cancer progression [4], [5]. A tight correlation of ferroptosis with various types of disorders in humans is corroborated by numerous studies. The high susceptibility of cancer cells to ferroptosis has been shown to offer a unique opportunity in the management of primary cancers. The most salient features of ferroptosis are intracellular lipid reactive oxygen species (ROS) accumulation and depletion of phospholipid (GPX4) in an iron-dependent manner [6], [7]. Several ferroptosis inducers developed on the basis of extensive research and substantial progress in the role of ferroptosis in oncology and tumor therapy [8]. RSL3, as a ferroptosis inducers, exhibits potent inhibitory activity of GPX4, which leads to lipid accumulation of peroxides [9], [10]. In cancer cells, RSL3 can facilitate ferroptosis induced cell death [6], [11]. Therefore, Ferroptosis shows great potential for application in cancer therapy [12], [13], [14].

In contrast to conventional drug delivery systems, NP based drug delivery systems enable greater water dispersion and stability of the drug [15]. Moreover, their specific size range (1–100 nm) can also substantially alter the in vivo distribution and metabolism of the drug. The drug release manner can be controlled by the proper design of the delivery vehicle, molecule type and loading method of the drug, thereby achieving optimal therapeutic efficacy [16]. More importantly, it is feasible to modify NP based drug delivery systems with targeted ligands, considering the specific receptor expression of cancer cells [17]. Because nanomaterials have distinct advantages in inducing ferroptosis in tumors [18], such as drug delivery to specific tumor sites, increased bioavailability, and decreased toxicity to normal tissues, ferroptosis nanomaterials offer a potential future in tumor therapy [19], [20].

Magnetic nanoparticles are used extensively in biomedicine, drug delivery, magnetic resonance imaging (MRI) and for tracking drugs [21]. They can be conjugated with drugs, proteins or genes, thereby serving as a therapeutic modality to enhance drug delivery to the target tissue. Fe3O4 superparamagnetic nanoparticles are a type of magnetic nanoparticles that are widely employed in drug delivery systems [22]. These nanoparticles exhibit remarkable magnetic properties and offer the advantage of easy surface modification and ligand binding, along with low toxicity, excellent biocompatibility, and biodegradability [23]. An external magnetic field can be employed to guide the drug-loaded magnetic nanoparticles to the desired tissue. Therefore, magnetite superparamagnetic nanoparticles are considered to be indispensable in drug delivery applications.

Fe3O4 nanoparticles require appropriate surface functionalization to avoid removal from the circulatory regime by the immune system [24], [25]. Polyethyleneimine (PEI) plays a crucial role in building multifunctional NPs due to its unique structural features. The presence of hydrophobic cavities in hyper-branched PEI enables efficient encapsulation of metal ions and metal oxides, resulting in stable NPs [26]. Hyaluronic acid (HA), a major component of polysaccharides and extracellular matrices, possesses high biodegradability and biocompatibility. Moreover, it serves as a wide-spectrum targeting ligand for cancer cells that over-express the CD44 gene. Further, HA modification of NPs can effectively reduce the attachment of plasma proteins and prolong their circulation time in vivo [27].

In this study, a sophisticated magnetic nanocube (Fe3O4[email protected]) was synthesized with the modification of polyethyleneimine (PEI) and hyaluronic acid (HA) on the surface of Fe3O4 nanoparticles. The Fe3O4 NPs selectively targeted tumor cells via an external magnetic field. HA, in association with CD44, further targeted tumor cells. The magnetic nanocubes loaded with RSL3 activated the ferroptosis signal transduction pathway by inhibiting the expression of Lactoferrin, FACL 4, GPX 4, Ferrtin, and by promoting ROS formation. In the acidic tumor microenvironment, the Fe3O4[email protected] nanoparticles exhibited increased stability and uniform dispersion. The drug delivery system significantly facilitated the ferroptosis process in hepatocellular carcinoma (HCC) (Scheme 1).