Hypoxia-responsive hybrid nanoparticles loaded with fingolimod and colistin against multidrug-resistant Klebsiella pneumoniae with mature biofilm

Abstract

Multidrug-resistant Klebsiella pneumoniae (MDR-KP) is characterized by high mortality and risk of nosocomial transmission, and biofilm constitutes the primary challenge in the treatment of its implant-associated and refractory pulmonary infections. Notably, the hypoxic microenvironment and the physical barrier of biofilm leading to the increased tolerance of the bacteria to antibiotics. Herein, a hypoxia-responsive hybrid nanoparticle (CHLip@FLD/COL) loaded separately with anti-biofilm candidate fingolimod (FLD) and antibiotic colistin (COL) is achieved targeting antibacterial efficacy against MDR-KP in vitro and in vivo. CHLip@FLD/COL is composed of hybridizing hypoxia-responsive lipids (HLipid) and lipid A targeting materials DSPE-mPEG-COL. HLipid is synthesized by hexadecanedioic acid esterified with nitroimidazole, while DSPE-mPEG is coupling with vector COL via amide reaction. The relative level of extracellular polymeric substances and the NIR-IIb sO₂ images of the infection site are used as indicators to establish mature biofilm models. CHLip@FLD/COL readily releases FLD and COL in hypoxic conditions, and its MIC against MDR-KP is only one-sixteenth of that when COL is used alone in vitro. The nanoparticle exhibits bacterial targeting ability and antibacterial effect in the pulmonary infection and biofilm infection mice models. Bacterial loads eliminated by $4{\mathrm{l}\mathrm{o}\mathrm{g}}_{10}$ CFU and $2{\mathrm{l}\mathrm{o}\mathrm{g}}_{10}$ CFU, respectively. The strategy provides a valuable reference for the treatment of refractory infections caused by MDR-KP.

Keywords

Hypoxia-responsive hybrid nanoparticle / Biofilm eradication / Fingolimod / Colistin / Multidrug-resistant Klebsiella pneumoniae

Conflicts of interest

The authors declare that there is no conflicts of interest.

Acknowledgments

This work was granted by National Key Research and Development Program of China (2021YFD1800900), Science and Technology Innovation Key R&D Program of Chongqing (CSTB2024TIAD-STX0038), National Natural Science Foundation of China (82574334, 32501226), Chongqing Science and Technology Commission (CSTB2023NSCQ-JQX0002), Special Fund for Youth Team of Southwest University (SWU-XJLJ202306), Chongqing Natural Science Foundation (CSTB2024NSCQ-MSX0547).

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ajps.2025.101107. The figures and tables with " S " before the serial number are included in the Supplementary material.

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