Multifunctional Cross-Linked Micelles for the Treatment of Acute Pneumonia Caused by MDR-KP with Reduced Cytokine Storms and Restored Metabolism and Immune Balance

Acute pneumonia caused by multidrug-resistant superbugs such as Klebsiella pneumoniae (MDR-KP) poses a severe public health threat for clinical patients with high mortality rate, where excessive cytokine storms and cellular dysfunction are the leading causes of death. More seriously, these superbugs have evolved specialized biological mechanisms that allow them to persist long-term within macrophages, rendering antibiotics and immunomodulators ineffective. Herein, a smart and multifunctional nanomicelle (NAC151-micelle), composed of colistin-NAD+-crosslinked drug and inhibitor H151, is developed for cooperatively killing of MDR-KP bacteria, alleviating hyperinflammatory cytokine storm, and improving metabolism and immune balance. NAC151-micelles optimized through in vitro bactericidal assays can smartly be responsive to the highly reduced environment within infected macrophages, allowing rapid release of active cargoes, including colistin and NAD+, thereby achieving efficient clearance of extra- and intracellular MDR-KP while improving cellular energy metabolism. Meanwhile, co-loaded H151 can cooperatively downregulate key inflammatory pathways of STING-TBK1-IRF3 and NF-κB p65 phosphorylation in macrophages with NAD+, reducing a cytokine storm. In MDR-KP-induced acute pneumonia infection, following intranasal tracheal administration, we observe a targeted accumulation in lung and significant downregulation of MDR-KP burden, together with drastically decreased cytokine storms with good safety. Furthermore, the immune balance in the lung is also greatly improved; pathological tissue injury is effectively repaired; and notably, functional macrophages are essential mediators of their therapeutic efficacy. Collectively, our study presents a safe and multifunctional therapeutic strategy (NAC151-micelles) for acute pneumonia caused by super-bacteria MDR-KP with rapid bacterial clearance, reduced cytokine storms, and improved metabolism and immune balance.