PEGylation Overcomes Pharmacological Barriers to Improve Systemic Pharmacokinetics and Therapeutic Efficacy of Phages against MDR Escherichia coli

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Systemic bacteriophage therapy against multidrug-resistant (MDR) Escherichia coli is fundamentally limited by rapid immune-mediated clearance, complement activation, and phagocytic sequestration, collectively constituting pharmacological barriers that restrict systemic bioavailability, shorten circulation half-life, and attenuate therapeutic efficacy.We hypothesized that PEGylation, by sterically shielding phage capsids from host immune clearance mechanisms, would enhance systemic stability, improve pharmacokinetic (PK) behavior, and augment therapeutic efficacy in vivo.Four lytic E. coli phages were covalently conjugated with 5-kDa mPEG-S-NHS, achieving >60% surface amine modification as confirmed by fluorescamine assay.PEGylation resulted in a ~1.5-5 log 10 reduction in infectious titer and modestly slowed adsorption kinetics but preserved latent period and burst size, confirming intact replication competence.In serum, wild-type phages were undetectable within 24-48 h, whereas PEGylated phages retained ~2-3 log 10 PFU ml -¹ at 24 h and persisted longer within RAW264.7 macrophages and HT-29 epithelial cells.In mice, PEGylation markedly increased systemic exposure (AUC0-∞ up to 50-fold), prolonged circulation, and reduced clearance >15-fold.In infected hosts, PEG-EC.W2-6 and PEG-EC.W15-4 achieved plasma titers up to 100-fold higher with >30-fold lower clearance, accelerating bacterial elimination (72 h vs 96 h).Despite partial IgG induction upon repeated dosing, PEGylated phages maintained superior PK and significantly suppressed infection-driven IL-6, IFN-γ, TNF-α, and IL-1β, normalizing cytokine profiles toward baseline.Overall, PEGylation markedly improves systemic persistence, intracellular stability, and immunomodulatory efficacy, representing a robust strategy to overcome PK barriers and optimize systemic phage therapy against MDR E. coli.

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