This study explores the use of bacteriophage proteins to guide nanodelivery systems for the targeted delivery of antibiotics to bacterial pathogens. The researchers developed two distinct nanodelivery systems, one targeting *Klebsiella pneumoniae* and the other targeting *Staphylococcus aureus*. These systems were created by conjugating bacteriophage receptor-binding proteins (RBPs) and cell-wall binding domains (CBDs) to biocompatible porous silica nanoparticles (UPSNS). The RBPs and CBDs were specifically designed to bind to the respective pathogens, enhancing the therapeutic efficacy of antibiotics such as rifampicin, imipenem, and ampicillin. In vivo experiments in mouse models of pneumonia caused by *K. pneumoniae* and *S. aureus* demonstrated that the nanodelivery systems significantly reduced bacterial loads and improved survival rates compared to free antibiotics. The systems also showed excellent biocompatibility and re-applicability, indicating their potential for treating difficult-to-treat infections. The study highlights the promising role of bacteriophage-derived targeting proteins in enhancing the effectiveness of antibiotic nanodelivery systems.This study explores the use of bacteriophage proteins to guide nanodelivery systems for the targeted delivery of antibiotics to bacterial pathogens. The researchers developed two distinct nanodelivery systems, one targeting *Klebsiella pneumoniae* and the other targeting *Staphylococcus aureus*. These systems were created by conjugating bacteriophage receptor-binding proteins (RBPs) and cell-wall binding domains (CBDs) to biocompatible porous silica nanoparticles (UPSNS). The RBPs and CBDs were specifically designed to bind to the respective pathogens, enhancing the therapeutic efficacy of antibiotics such as rifampicin, imipenem, and ampicillin. In vivo experiments in mouse models of pneumonia caused by *K. pneumoniae* and *S. aureus* demonstrated that the nanodelivery systems significantly reduced bacterial loads and improved survival rates compared to free antibiotics. The systems also showed excellent biocompatibility and re-applicability, indicating their potential for treating difficult-to-treat infections. The study highlights the promising role of bacteriophage-derived targeting proteins in enhancing the effectiveness of antibiotic nanodelivery systems.