# A Hemoglobin-Based Nanoparticle Delivery System Enhances the Pharmacokinetics and Efficacy of Tigecycline in Klebsiella pneumoniae Infections

## TL;DR

This study creates a new drug delivery system using hemoglobin nanoparticles to improve tigecycline's effectiveness against Klebsiella pneumoniae infections.

## Contribution

The first report of tigecycline loaded onto hemoglobin nanoparticles for targeted antibiotic delivery.

## Key findings

- TIG–HBNP nanoparticles showed enhanced targeting to Klebsiella pneumoniae in vitro and in vivo.
- The system improved tigecycline's pharmacokinetics and antibacterial activity against drug-resistant K. pneumoniae.
- Hemoglobin nanoparticles demonstrated favorable stability, safety, and drug-loading efficiency.

## Abstract

Objective: This study aims to engineer a tigecycline–hemoglobin nanoparticle (TIG–HBNP) system to enhance the targeting effect of tigecycline (TIG) on Klebsiella pneumoniae, thereby improving its antibacterial efficacy. Impact Statement: This study represents the first report of loading TIG onto hemoglobin (HB) nanoparticles. This system utilizes the iron dependence of K. pneumoniae to enhance the targeting ability of TIG and increase the drug concentration at the infection site, thereby enhancing the antibacterial activity and providing a promising strategy for combating drug-resistant gram-negative bacterial pneumonia. Introduction:
K. pneumoniae is a gram-negative bacillus that causes severe primary pneumonia with high pathogenicity and increasing drug resistance. TIG is a key therapeutic option, but its clinical effectiveness is limited by extensive systemic distribution and insufficient drug concentration at infectious foci. HB serves as a promising protein nanocarrier and provides iron, an essential nutrient for K. pneumoniae growth, suggesting great potential for targeted antibiotic delivery. Methods: Molecular docking was performed to analyze the binding affinity and interaction between HB and TIG. TIG–HBNP was fabricated via a drug–protein self-assembly approach. The nanoparticles were characterized in terms of particle size, zeta potential, drug-loading efficiency, morphology using transmission electron microscopy and atomic force microscopy, stability, and biocompatibility. Targeting capability was evaluated. Pharmacokinetic profiles and antibacterial activity were further assessed. Results: Molecular docking verified stable binding between TIG and HB. TIG–HBNP exhibited a uniform spherical morphology, a particle size of approximately 200 nm, a negative surface charge, and a drug-loading efficiency exceeding 20%. The nanoparticles showed favorable stability and safety. Enhanced targeting to K. pneumoniae was confirmed in both in vitro and in vivo models. Improved pharmacokinetic behavior and enhanced antibacterial activity against K. pneumoniae were also observed. Conclusion: TIG–HBNP enhances TIG’s therapeutic efficacy against K. pneumoniae infections. Furthermore, HB holds promise as a versatile carrier for diverse antibiotics, offering a scalable platform to combat multidrug-resistant pathogens.