CCR2-overexpressing Biomimetic Carrier-free Nanoplatform for Enhanced Cascade Ferroptosis Tumor Therapy

Therapeutic approaches targeting apoptosis have been the mainstream of antitumor therapy researches [1,2]. However, the therapeutic effect based on anti-apoptotic mechanisms is not always satisfactory. Ferroptosis, an emerging non-apoptotic programmed cell death characterized by iron-dependent lipid peroxide (LPO) accumulation and altered redox homeostasis, is related to regulating various biological pathways, including iron, amino acid, and lipid metabolism [3], [4], [5]. Ferroptosis has become a hot topic and gradually attracted extensive attention [6], [7], [8]. It can avoid therapeutic resistance related to apoptotic pathways by regulating intracellular redox homeostasis, which could inspire clinical practice, especially for treating metastatic or drug-resistant tumors with arrested apoptosis [9].

Currently, several ferroptosis-based nanotherapies have been developed for cancer treatment. Most nanodrugs utilize organic or inorganic carriers to combine and deliver iron-source or ferroptosis-inducing agents [10], [11], [12], [13], [14], [15], [16]. For example, Yang et al. designed a [email protected] nanoreactor for initiating synergistic CDT-ferroptosis tumor therapy by loading DHA into the metal-organic framework [17]. Wei et al. constructed [email protected]/B nanodrugs loading DOX and L-buthionine sulfoximine into gold nanocage to evoke ferroptosis [10]. Wu et al. designed a cisplatin prodrug-loaded manganese-deposited iron oxide nanoplatform to generate ROS for enhancing ferroptosis [18]. However, these carrier-based nanoplatforms inevitably face obstacles, such as degradation, metabolism, and immunogenicity [19,20]. In addition, the complex synthetic procedures and low drug loading efficacy of carry-assisted nanoplatforms have become restrictions of large-scale industrial preparation, limiting their availability and applicability [21]. Carrier-free nanodrugs formed by self-assembly of the active drug itself can bypass these shortcomings. These nanodrugs are simple to synthesize, avoiding the biosafety issues of complex chemical modifications and additional excipients [22,23]. Currently, few carrier-free nanoplatforms have been reported for cascade ferroptosis tumor therapy.

Hemin, an iron-based porphyrin molecule, has been approved by the US Food and Drug Administration as an iron supplement. It is a purified form of endogenous heme in vitro, decomposed by heme oxygenase (HO-1) in the cytoplasm to release Fe ions [24]. Eastin, a system Xc inhibitor, plays a role in the induction of ferroptosis and promotes HO-1 expression [25,26]. In addition, there are π-conjugated structures with numerous C-C double bonds and electron-rich heterocycles in both structures of hemin and erastin, which are conducive to the formation of π-π stacking interactions between the two small molecule drugs. The assembled nanospheres can improve the solubility of the two components and do not affect their respective functions [27].

Herein, hemin and erastin were assembled through supramolecular interaction to form a carrier-free nanomedicine (HESN). Then, HESN was co-extruded with CCR2-overexpressing macrophages to prepare a biomimetic carrier-free nanoplatform ([email protected]) [28,29]. [email protected] would be taken up by cancer cells via the CCR2-CCL2 axis, disrupted by the acidic intracellular environment, and further decomposed into hemin and erastin. Erastin could induce ferroptosis by inhibiting system XC−, and hemin could be further broken down by HO-1, increasing the intracellular Fe2+ concentration. Meanwhile, erastin could enhance the activity of HO-1, further promoting Fe2+ release and inducing ferroptosis. Therefore, [email protected] could accumulate in the tumor site and inhibit primary and metastatic tumors. The cascade ferroptosis treatment elicits powerful anticancer effects both in vitro and in vivo, thus showing promise for fighting cancers (Scheme 1).

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