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.