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Conventional antibiotic therapies are increasingly constrained by limited efficacy and the growing prevalence of antimicrobial resistance, highlighting the urgent need for innovative therapeutic strategies capable of concurrently targeting multiple pathogenic mechanisms. In this study, we developed a carrier\u2010free nanomedicine that co\u2010delivers two natural compounds with synergistic pharmacological activity. Using a self\u2010assembly approach, Baicalein (BAI) and Resveratrol (RES) were formulated into stable BAI\u2010RES nanoparticles (BR NPs), designed to enhance aqueous solubility and improve therapeutic outcomes. BR NPs demonstrated preferential accumulation in pulmonary macrophages of pathogen\u2010infected mice, and enabled pH\u2010responsive drug release within the inflammatory microenvironment. Mechanistically, BR NPs modulated inflammatory and immune responses by suppressing M1 macrophage polarization, reducing excessive neutrophil infiltration, and mitigating oxidative stress through the regulation of critical signaling pathways, such as Toll\u2010like receptor, TNF, and HIF\u20101 pathways. These findings indicate that carrier\u2010free BR nanoparticles exhibit synergistic effects, macrophage\u2010targeting and controlled\u2010release properties, as well as multi\u2010target and multi\u2010pathway therapeutic benefits, thus offering a novel and promising strategy for the treatment of pneumonia induced by pathogens.<\/jats:p>","DOI":"10.1002\/ptr.70211","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T05:52:16Z","timestamp":1768801936000},"page":"1099-1116","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Self\u2010Assembled Baicalein\u2013Resveratrol Nanomedicine Synergistically Modulates Multiple Pathways to Alleviate Pathogen\u2010Induced Pneumonia"],"prefix":"10.1002","volume":"40","author":[{"given":"Fuyun","family":"Chi","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy and Tianjin Key Laboratory 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