Nanoflower-Mediated Gallium-Protoporphyrin IX Complex for Intracellular Antibacterial and Immunomodulatory Effects in Macrophage-Targeted Therapy

Intracellular bacterial infections are challenging due to immune evasion and antibiotic resistance, especially within macrophages harboring dormant bacteria. Here, a synergistic antibacterial strategy is presented using the PG3M@GaPP nanoflowers, which integrate immune modulation, iron metabolism disruption, and antibacterial photodynamic therapy (APDT) to eliminate intracellular bacteria. This nanoflower encapsulates a gallium-protoporphyrin IX complex (GaPP) within mannose-functionalized poly-l-lysine dendrimers (PG3M), enabling targeted delivery to macrophages via mannose receptor recognition. PG3M@GaPP promotes macrophage polarization to the anti-inflammatory M2 phenotype, enhancing immune modulation and bacterial uptake. The platform's positive charge facilitates endosomal escape, releasing GaPP in the acidic intracellular environment, where free iron ions compete with gallium ions to form the iron-protoporphyrin IX complex (FePP). This disrupts the gallium/iron ion balance, enhancing the Trojan horse effect of gallium ions and inducing iron metabolism-dependent bacterial death. Additionally, laser activation of GaPP generates reactive oxygen species (ROS), further amplifying bacterial killing via APDT. <i>In vitro</i> and <i>in vivo</i> experiments show that PG3M@GaPP outperforms both free GaPP and commercial antibiotics in eliminating intracellular bacteria. These nanoflowers offers an alternative, nonantibiotic approach to combat intracellular infections, addressing drug resistance and providing a promising platform for antibacterial therapies.