Phage therapy for multidrug-resistant pulmonary infections: bridging precision matching, lung delivery, host immunity, and clinical translation

Abstract

Chronic pulmonary infections caused by multidrug-resistant (MDR) bacteria are a growing global health problem, and the declining effectiveness of conventional antibiotics increases the need for alternative antimicrobial strategies. Unlike broad-spectrum antibiotics, bacteriophages are highly specific, and their use therefore offers not only antibacterial activity but also the possibility of reshaping the airway microbial ecosystem in a targeted manner. In this review, we reframe phage therapy as a precision microbiome-modulating strategy for chronic pulmonary infections. We first review precision pathogen identification and phage-host matching, then discuss formulation engineering for pulmonary delivery, and then examine the interactions between phages and host immune barriers. We further analyze how phage therapy may selectively deplete MDR pathogens while sparing the commensal microbiota and how it may remodel the airway microbial ecosystem, and we critically evaluate the clinical evidence, distinguishing preclinical data, case-based evidence, observational studies, and controlled trials. By integrating these dimensions, we identify the main scientific and technical challenges and evidence gaps that currently limit clinical implementation, and we discuss strategies that could support the development of safe, effective, and clinically applicable phage-based therapies for chronic pulmonary infections.