Charge-Adaptive Nanoparticle Attenuates Inflammation via Targeting Neutrophil Extracellular Traps (NETs) and Breaking NETs–Macrophage Crosstalk

Cationic materials serve as a critical strategy for capturing neutrophil extracellular traps (NETs), which are structured around negatively charged DNA and represent a key pro-inflammatory pathogenic factor. However, their application is constrained by the inherent cytotoxicity of positive charges. Here, we develop a charge-adaptive neutrophil-targeted nanoparticle system (CPS@BA) through conjugating sialic acid (SA) to carboxymethyl chitosan (CMCS)–polyethylenimine (PEI) copolymer and physically encapsulating the calcium chelator BAPTA-AM (BA). This smart nanoparticle exhibits charge adaptability, dynamically and reversibly responding to acidic transitions in the pathological milieu. When sensing the acidic milieu on activated neutrophil surfaces, CPS@BA reverses its charge from negative to positive, thereby facilitating rapid NETs capture. Once inflammation is resolved and the pH returns to neutral, the residual CPS@BA reversibly switches back to biocompatible negative charges, effectively minimizing cationic biotoxicity. Meanwhile, charge adaptation triggers a cascade of size adaptation, enabling CPS@BA to ingeniously regulate the release of BA, which could suppress further NETs formation by chelating intracellular Ca2+ and inhibiting PAD4 enzymatic activation. As a result, the simultaneous clearance and inhibition of NETs effectively block the detrimental crosstalk between NETs and macrophages by interrupting the CXCL3–CXCR2 axis. This intervention rescues mitochondrial dysfunction and promotes metabolic reprogramming in pro-inflammatory macrophages, ultimately alleviating inflammatory bone resorption in experimental periodontitis. Overall, this study presents a secure and reversible charge-adaptive strategy capable of simultaneously clearing and inhibiting NETs, holding broad potential for the treatment of all free DNA-driven inflammatory diseases.