NIR‐II‐Triggered Cascade Nanoplatform Combats Biofilms Through CO Release and Macrophage Reprogramming

ABSTRACT Bacterial biofilms represent a major clinical challenge due to their inherent tolerance to antimicrobials and ability to subvert host immune responses. The dense extracellular polymeric substance (EPS) matrix not only limits the penetration of antibacterial agents but also polarizes macrophages toward an anti‐inflammatory M2 phenotype, further impairing bacterial clearance. To address these dual barriers, we developed a near‐infrared‐II (NIR‐II) light‐responsive nanoplatform, termed MCD (MnCO@N‐C@Dex). Its design integrates a nitrogen‐doped carbon nanoshell (N‐C NSs) core loaded with a manganese carbonyl (MnCO) prodrug and an outer dextran coating. Under 1064 nm irradiation, the N‐C NSs simultaneously generate localized hyperthermia for photothermal therapy (PTT) and produce hydroxyl radicals (·OH), which subsequently trigger on‐demand carbon monoxide (CO) release from MnCO, establishing a cascade PTT/CO bactericidal process. Concurrently, the dextran coating enhances biofilm penetration and reprograms macrophages toward the pro‐inflammatory M1 phenotype, thereby boosting antibacterial immunity. MCD shows efficient biofilm penetration and potent disruption of Staphylococcus aureus biofilms in vitro. In a mouse subcutaneous abscess model, MCD further demonstrates strong antibiofilm and immunomodulatory effects, leading to effective infection clearance. This work demonstrates that combining NIR‐II‐triggered gas therapy with targeted immune reprogramming offers a promising and safe strategy for treating biofilm‐associated infections.