An innate immunity-reprogramming hydrogel nips postoperative adhesions in the bud via transforming pathological healing into physiological recovery.

Abstract

Postoperative adhesions are frequent and challenging complication lacking effective prevention. Evidence indicates that innate immune responses triggered by surgical trauma critically influence whether normal tissue repair progresses to pathological adhesions, highlighting early inflammatory responders as key intervention targets. Here, we successfully transformed natural hyaluronic acid (HA) into a potent innate inflammation modulator through a one-step sulfoxide-conjugation strategy. The resultant sulfoxide-conjugated HA (SOHA) demonstrated near-complete prevention of adhesion formation across multiple clinically relevant animal models, including those for secondary injury, long-term abdominal adhesions, and pericardial-pleural adhesions. Mechanistic investigations reveal that, unlike traditional physical barriers that primarily inhibit the late-stage adhesion of activated fibroblasts, SOHA addresses postoperative adhesions at their inception by reprogramming early innate inflammatory responses. It shifts the neutrophil cell death mode from acute, pro-inflammatory NETosis to more regulated, immunologically silent apoptotic process. Furthermore, it selectively restrains the early accumulation of large peritoneal macrophages (LPMs) in damaged tissues, redirecting them towards a reparative M2-like phenotype through the efferocytic clearance of apoptotic neutrophils, thereby promoting their timely involvement during the resolution phase of inflammation. This dual regulation of innate immunity effectively interrupts the postoperative inflammatory cascade and subsequent fibrotic progression, thus effectively shifting the pathological tissue repair into physiological healing.