Mannose‐Modified Zif‐8 Nanoparticles Promote Macropinocytosis‐Mediated Dendritic Cell Uptake and Induce Potent Humoral/Cellular Immunity Against Klebsiella pneumoniae

ABSTRACT Zeolitic imidazolate framework‐8 (ZIF‐8) has limitations in vaccine delivery, including poor targeting and rapid clearance. The outer membrane phosphoporin pore protein (PhoE) has been validated as a promising antigen against Klebsiella pneumoniae . We developed a mannose (M)‐functionalized ZIF‐8 nanoparticle (PhoE@M‐ZIF‐8) via polyethylene glycol (PEG) conjugation and mannose conjugation to enable targeted delivery to antigen‐presenting cells (APCs). PhoE@M‐ZIF‐8 exhibited pH‐responsive antigen release and was internalized via mannose receptor‐mediated macropinocytosis, promoting dendritic cell maturation (CD11c + CD86 + upregulation) and inducing a balanced T helper type 1/type 2 (Th1/Th2) immune response. In vivo, PhoE@M‐ZIF‐8 achieved potent protection against lethal Klebsiella pneumoniae challenge with only two immunizations, showing high survival rates and favorable biosafety. This work presents a versatile APC‐targeting platform for effective subunit vaccine development.