As a major cause of human mortality, cancer remains an immense challenge for which discovering a definitive cure is still elusive [1]. Tumor cells exhibit distinct characteristics that are different from those of normal cells, emphasizing the necessity of therapeutic approaches tailored to their unique properties. The tumor microenvironment (TME) is typically characterized by weak acidity [2], [3], abnormal metabolism, and high levels of hydrogen peroxide concentration [4]. Therefore, the utilization of inducing ferroptosis of tumor cells emerges as a highly promising strategy in cancer therapy. It triggers lipid peroxidation accumulation by the generation of highly cytotoxic ·OH radicals from endogenous H2O2 in the tumor cells through the Fenton reaction [5], [6], [7], [8]. Therefore, therapeutic modality based on ferroptosis exhibits high tumor-specificity and low systemic side effects [9], [10]. However, it suffers from poor therapeutic outcomes caused by the insufficient H2O2 level in tumor cells and randomness in ROS production [11], [12], [13].

Mitochondria, the subcellular organelles with double-layer membranes, are the primary sources of reactive oxygen species (ROS) production in cells, with 90 % of cellular ROS originating from mitochondria [4], [14], [15]. Any abnormalities in the structure and function of mitochondria can contribute to the development of various diseases, including cancer [16]. In tumor cells, the structure and function of mitochondria differ significantly from those of normal cells [17]. This includes mutations in mitochondrial DNA (mt DNA) that can impair or inhibit oxidative phosphorylation (OXPHOS), alter expression of mitochondrial proteins [18], and elevate ROS levels [19]. The exposed structure and limited DNA repair capacity of the mitochondrial mutant genome in tumor cells make them highly vulnerable to ROS [20]. Furthermore, the mitochondrial transmembrane potential in tumor cells can range from −180 mV to −220 mV, as compared to −140 mV potential in normal cells. This significant difference facilitates the uptake and accumulation of lipophilic cations within tumor cell mitochondria [21], [22]. In recent years, the development of mitochondria-targeted nanosystems for the precise delivery of therapeutic agents to mitochondria has garnered considerable attention as a promising approach in cancer therapy [23], [24]. This approach not only reduces the potential off-target toxic side effects on normal tissues, but also enhances the bioavailability of drugs at the target site, enabling the use of lower dosages [25]. Additionally, mitochondrial targeting has been reported to prevent multidrug resistance and tumor recurrence in cancer therapy, as mitochondria-targeted drugs are less easily effluxed than those randomly distributed in the cytoplasm [26]. It is also clear that organelles such as mitochondria, endoplasmic reticulum and lysosomes play a vital role in the development of ferroptosis [27]. Specifically, mitochondria undergo notable morphological and functional alterations during ferroptosis and represent a promising target. Therefore, the development of mitochondrial-targeted nanomedicine which could specifically enhance the ROS level of mitochondria, thereby strengthening the ferroptosis effect of tumors, is of great value for clinical application of ferroptosis-based therapy.

In this paper, we devised a novel mitochondrial targeted nanoagent (PNE-PEG-TPP-Fe) that can enhance the concentration of hydrogen peroxide within mitochondria. This nanoagent used polynorepinephrine (PNE) as carriers which was derived from norepinephrine (NE). The synthesis process and action mechanism were shown in Scheme 1. These PNE carriers were modified with methoxypoly (ethylene glycol) amine (mPEG-NH2) to enhance the stability and dispersibility of the nanoparticles. Furthermore, we introduced 3-carboxypropyl-triphenylphosphonium bromide (TPP-COOH) to confer mitochondrial targeting capabilities, resulting in the synthesis of PNE-PEG-TPP-Fe nanoagent. The PNE-PEG-TPP-Fe nanoparticles possess a remarkable ability to selectively target and accumulate in the mitochondria due to the presence of electropositive triphenylphosphine (TPP), a small lipophilic cationic molecule. More importantly, the PNE carriers can significantly enhance the concentration of hydrogen peroxide in mitochondria by catechol oxidation. Within the mitochondria of tumor cells, the nanoagent catalyzes the abundant H2O2 through the Fenton reaction and then generates a significant amount of ROS, which can attack the structural integrity of the mitochondrial membrane and disrupt mitochondrial function. This process leads to the accumulation of lipid peroxides and enhances the lethal effect of ferroptosis in tumor cells. These findings highlight the potential of the PNE-PEG-TPP-Fe nanoagent as a promising therapeutic approach for cancer treatment, capitalizing on the specific features of tumor cell mitochondria and the ferroptosis pathway.