Natural bioactive polyphenols contain many phenolic hydroxyl groups, possessing anti-inflammation, antibacterial, anti-tumor and many other pharmacological activities [1,2]. Because of their inhibition effect on tumor cells, low toxicity, and no mutagenicity, natural polyphenols have attracted widespread attention as alternatives to conventional chemotherapy drugs with high toxicity to normal cells [[3], [4], [5], [6]]. However, the poor water solubility, low bioavailability, and no selectivity to tumor cells, greatly diminish their therapeutic effect [[7], [8], [9], [10], [11], [12]]. Meanwhile, the single function and non-targeted release also limit their further application in the biomedical field [[13], [14], [15], [16]]. Inspired by the abundant phenol hydroxyl groups on polyphenols, researchers employ metal ions to coordinate with polyphenols, producing metal-phenolic networks (MPNs), which have attracted much attention as versatile nanoparticles (NPs) or coatings for combination therapy [[17], [18], [19], [20], [21], [22], [23]]. In MPNs, according to the demand, different therapeutic metal ions can be introduced and coordinate with functional polyphenols to achieve multimode therapy [24,25]. When constructing MPNs, the number of metal coordination sites of polyphenols plays a key role [26,27]. In flavonoid polyphenols and other phenolics, the metal coordination sites usually refer to the groups, with which metal ions tend to coordinate to form stable six- or five-membered rings, for example, the 5-hydroxyl and 4‑carbonyl groups, the 3-hydroxyl and 4‑carbonyl groups, and the ortho phenolic hydroxyl groups (Fig. S1a) [28,29]. It is reported that the design of MPNs prefers to employ multi-valency polyphenols with multi-metal coordination sites, which can coordinate with metal ions to form infinite coordination networks, then assemble into multifunctional responsive nanomaterials [[30], [31], [32]].

However, there are still many single valency polyphenols with only one coordination site for metal complexation, which possess favorable pharmacological activities but always fail to be involved in MPNs because of the inextensibility of single metal coordination site. Researchers have made some efforts to explore the methods for single valency polyphenols constructing MPNs [33,34]. However, these methods always require complex procedures or introduce undegradable polymers, which need further improvements. Multifunctional β-FeOOH NPs have been investigated for tumor diagnosis and therapy, because of the potential for magnetic resonance (MR) imaging and the biocompatible drug nanocarriers [35,36]. In the formation process of β-FeOOH NPs, the ferric ions (Fe3+) in an aqueous solution sequentially undergo coordination, hydrolysis, polymerization and precipitation, in which H2O molecules coordinate with Fe3+, and lose H+ to form Fe-OH-Fe bonds to extend the coordination networks [37]. The interesting synthesis process of β-FeOOH provides a refreshing perspective to design single valency polyphenols constructing MPNs. H2O molecules in the hydrolysis process of Fe3+ can be regarded as the two-coordinated blocks, which can be utilized to connect the Fe3+-single valency polyphenol complexes, by forming Fe-FeOOH-Fe-polyphenol structures. Also, the FeOOH can provide abundant -OH groups for anchoring Fe3+-polyphenol complexes. Therefore, exploring to prepare single valency polyphenol-constructed MPNs with the assistance of FeOOH will be feasible.

Herein, a FeOOH assisted preparation method is proposed to achieve the single valency polyphenol-constructed MPNs. In this strategy, the FeOOH is introduced as a building block to connect the inextensible Fe3+-single valency polyphenol complexes by forming Fe(H2O)x-polyphenoly complexes, thus producing Fe3+-polyphenol networks-coated FeOOH NPs ([email protected] NPs). Taking the single valency apigenin (Ap) (Fig. S1b) as an example, Fe(H2O)x-Apy complexes are foremost formed. Initially, the Fe(H2O)6 (y = 0) complexes hydrolyze to generate FeOOH with -OH groups, on which the Fe3+-Ap complexes can be anchored, generating a layer of MPNs on the surface of FeOOH. Subsequently, the Fe(H2O)x-Apy (y ≠ 0) complexes can form extendible-coordinated Fe-FeOOH-Fe-polyphenol structures, benefiting from the connection of FeOOH, which is produced by the hydrolysis of Fe(H2O)x. With the assistance of FeOOH, the Fe3+-Ap networks-coated FeOOH NPs ([email protected] NPs) are successfully fabricated. The [email protected] NPs can be stimulated by overexpressed reductive glutathione (GSH) in the tumor microenvironment (TME), and reactively release Ap and generate Fe2+. The released Ap molecules can block the tumor cell cycle in the G2/M phase, inhibiting cell proliferation, and induce cell apoptosis [38]. In addition, the GSH depletion and the increase of Fe2+ level significantly facilitate the production of ·OH and the downregulation of glutathione peroxidase 4 (GPX4), jointly leading to the accumulation of lipid peroxidation (LPO), which eventually induces ferroptosis in tumor cells [[39], [40], [41], [42], [43], [44]]. Furthermore, the FeOOH core can shorten transverse relaxation time and have the potential to act as a T2-weighted MR imaging contrast agent [45]. Therefore, the GSH-responsive [email protected] NPs can exhibit excellent apoptosis and ferroptosis combined tumor therapy effects guided by T2-weighted MR imaging. This study demonstrates a strategy for the construction of MPNs employing single valency polyphenols, presenting a significant advancement in MPNs design.