Neutrophil Extracellular Traps‐Inhibiting and Fouling‐Resistant Polysulfoxides Potently Prevent Postoperative Adhesion, Tumor Recurrence and Metastasis

Abstract Peritoneal metastasis (PM) is considered one of the most dreaded forms of cancer metastases for both patients and physicians. Aggressive cytoreductive surgery (CRS) is the primary treatment for peritoneal metastasis. Unfortunately, this intensive treatment frequently causes clinical complications, such as postoperative recurrence, metastasis, and adhesion formation. Emerging evidence suggest that neutrophil extracellular traps (NETs) released by inflammatory neutrophils contribute to these complications. Effective NET‐targeting strategies thus show considerable potential in counteracting these complications but remain challenging. Here, we synthesized and screened one type of sulfoxide‐containing homopolymer, PMeSEA, with potent fouling‐resistant and NET‐inhibiting capabilities. Hydrating sulfoxide groups endow PMeSEA with superior non‐fouling ability, significantly inhibiting protein/cell adhesion. Besides, the polysulfoxides can be selectively oxidized by ClO – which is required to stabilize the NETs rather than H 2 O 2 , and ClO – scavenging effectively inhibits NETs formation without disturbing redox homeostasis in tumor cells and quiescent neutrophils. As a result, PMeSEA potently prevents postoperative adhesions, significantly suppresses peritoneal metastasis, and shows synergetic antitumor activity with chemotherapeutic 5‐Fluorouracil. Moreover, coupling aggressive cytoreductive surgery (CRS) with PMeSEA potently inhibits CRS‐induced tumor metastatic relapse and postoperative adhesions. Notably, PMeSEA exhibits low in vivo acute and subacute toxicities, implying significant potential for clinical postoperative adjuvant treatment. This article is protected by copyright. All rights reserved