Self‐Assembled Baicalein–Resveratrol Nanomedicine Synergistically Modulates Multiple Pathways to Alleviate Pathogen‐Induced Pneumonia

Pathogen-induced pneumonia represents a major global health threat, owing to its high morbidity and mortality. 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-free nanomedicine that co-delivers two natural compounds with synergistic pharmacological activity. Using a self-assembly approach, Baicalein (BAI) and Resveratrol (RES) were formulated into stable BAI-RES nanoparticles (BR NPs), designed to enhance aqueous solubility and improve therapeutic outcomes. BR NPs demonstrated preferential accumulation in pulmonary macrophages of pathogen-infected mice, and enabled pH-responsive 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-like receptor, TNF, and HIF-1 pathways. These findings indicate that carrier-free BR nanoparticles exhibit synergistic effects, macrophage-targeting and controlled-release properties, as well as multi-target and multi-pathway therapeutic benefits, thus offering a novel and promising strategy for the treatment of pneumonia induced by pathogens.