Photothermal enhanced polyphenol-based nanofibers ameliorate catalytic efficiency of ferroptosis for synergistic tumor therapy

Ferroptosis is an emerging antitumor treatment modality with the superiority for evading apoptotic cell death pathway. However, how to elevate catalytic efficacy of Fe2+-mediated Fenton reaction and efficiently elicit ferroptosis remain enormously challenging. Herein, inspired by hyperthermia-enhanced Fenton reaction kinetics, we firstly designed iron-polyphenol-aspirin-coordinated nanochelates for photothermal-enhanced ferroptosis antitumor immunotherapy. Specifically, we modulated optimal mass feeding ratio of gallic acid (GA), aspirin (ASA), Fe (II) and polyvinylpyrrolidone (PVP) to construct novel nanofibrous GA-ASA-Fe (II) metalchelates named GAFs. The variations in size and structure allowed the nanomedicines to avoid the risk of premature renal clearance in vivo, compared with the reported ultrasmall GA-Fe (II) nanocomplexes (GFs). Under NIR laser irradiation, GAFs could constantly amplify toxic hydroxyl radicals (& BULL;OH) generation and deplete excessive GSH to induce more accumulation of lethal lipid peroxidation (LPO), thereby triggering ferroptosis pathway in vitro and in vivo. Besides, the introduction of ASA could inhibit cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2), in combination with photothermal-enhanced ferroptosis tumor therapy to induce immunogenic cell death (ICD), promote maturation of dendritic cells (DCs) and activate cytotoxic T cells for synergistic antitumor immuno-therapy. GAFs with laser irradiation exhibited the capacity of inhibition of pulmonary metastasis. This work presented a strategy for incorporating small molecule immunomodulator into the metal-polyphenolic coordi-nation to ameliorate its deficiencies, thereby inspiring a new design concept for tumor treatment.

Automated summary

In this study, iron-polyphenol-aspirin-coordinated nanochelates were designed for photothermal-enhanced ferroptosis antitumor immunotherapy. These nanochelates could constantly generate toxic hydroxyl radicals and induce lethal lipid peroxidation, triggering ferroptosis pathway both in vitro and in vivo. In addition, they could inhibit inflammatory factors and promote immune cell activation for better antitumor efficacy.