Piezoelectric catalysis “nets-breaking and source-rescuing”: targeting and degrading neutrophil extracellular traps restores arginine metabolism for enhanced antitumor immunotherapy

Mechanistic Insight: Identified a NETs-mediated arginine depletion pathway that suppresses T cell infiltration and effector function in the tumor microenvironment (TME). • Biomimetic Design: Developed a neutrophil membrane-camouflaged piezoelectric nanodrug (gZn-PCN@NEM) for targeted delivery to tumor sites. • Targeted NETs Degradation: Piezoelectric catalysis enables efficient degradation and functional inactivation of NETs within the TME. • Barrier Breakdown: Elimination of NETs dismantles the physical barrier, significantly enhancing T cell infiltration into tumors. • Metabolic Restoration: NETs disruption restores local arginine levels in the TME, providing essential metabolic support for T cell proliferation and activation. • Enhanced Immunotherapy: Synergistic regulation of the physical barrier and arginine metabolism markedly enhances T cell-mediated antitumor immune responses. • Therapeutic Strategy: This work proposes a dual-function immunomodulatory strategy integrating NETs disruption with arginine rescue to overcome tumor immunosuppression. Arginine depletion in the tumor microenvironment (TME) directly deprives T cells of key metabolic substrates required for proliferation and differentiation, thereby inhibiting their antitumor effects. This process is closely associated with neutrophil extracellular traps (NETs). Under inflammatory stimulation, neutrophils generate hypochlorous acid (HClO) by intracellular enzymes and release chromatin and proteases to form NETs. Notably, arginase-1 (ARG1) within NETs accelerates arginine degradation, impairing the metabolic supply of T cells and forming the immunosuppressive TME. Herein, we construct a piezoelectric catalytic nanodrug gZn-PCN@NEM to degrade NETs by doping polymerized carbon nitride (PCN) nanosheets with gradient Zn 2+ and coating them with neutrophil membranes (NEM). This biomimetic camouflage enables neutrophils to rapidly internalize gZn-PCN@NEM and transport it to the tumor site. Under ultrasonic (US) stimulation, gZn-PCN@NEM decomposes HClO in NETs to produce chlorine radicals (Cl·), which induce DNA double-strand breaks of tumor cells, thereby efficiently killing them. The decomposition of HClO triggers the structural collapse of NETs and functional inactivation of ARG1, thereby restoring arginine levels in the TME and promoting T cell proliferation and activation. This work proposes a piezoelectric-catalytic “nets-breaking and source-rescuing” strategy to rescue arginine by degrading NETs, providing a promising approach for enhancing cancer immunotherapy.