Wrecking neutrophil extracellular traps and antagonizing cancer-associated neurotransmitters by interpenetrating network hydrogels prevent postsurgical cancer relapse and metastases

Tumor-promoting niche after incomplete surgery resection(SR)can lead to more aggressive local progression and distant metastasis with augmented angiogenesis-immunosuppressive tumor microenvironment(TME).Herein,elevated neutrophil extracellular traps(NETs)and cancer-associated neurotransmitters(CANTs,e.g.,catecholamines)are firstly identified as two of the dominant inducements.Further,an injectable fibrin-alginate hydrogel with high tissue adhesion has been constructed to specifically co-deliver NETs inhibitor(DNase I)-encapsulated PLGA nanoparticles and an unselectiveβ-adrenergic receptor blocker(propranolol).The two components(i.e.,fibrin and alginate)can respond to two triggers(thrombin and Ca2+,respectively)in postoperative bleeding to gelate,shaping into an interpenetrating network(IPN)featuring high strength.The continuous release of DNase I and PR can wreck NETs and antagonize catecholamines to decrease microvessel density,blockade myeloid-derived suppressor cells,secrete various proinflammatory cytokines,potentiate natural killer cell function and hamper cytotoxic T cell exhaustion.The reprogrammed TME significantly suppress locally residual and distant tumors,induce strong immune memory effects and thus inhibit lung metastasis.Thus,targetedly degrading NETs and blocking CANTs enabled by this in-situ IPN-based hydrogel drug depot provides a simple and efficient approach against SR-induced cancer recurrence and metastasis.