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

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.