Dual-drug nanoplatform HPA@NPs reprograms the fibrotic microenvironment by suppressing EMT and M2 macrophage polarization in pulmonary fibrosis.

Pulmonary fibrosis (PF) is a progressive and lethal interstitial lung disease, characterized by excessive extracellular matrix deposition and architectural distortion of the lung parenchyma. Its pathogenesis involves interconnected pathological events, including dysregulated epithelial-mesenchymal transition (EMT), chronic inflammation driven by M2-polarized macrophages, and abnormal fibroblast activation. These intertwined mechanisms contribute to the limited efficacy of current anti-fibrotic therapies, which often fail to achieve lesion-specific targeting and disease reversal. Moreover, the clinical utility of existing drugs is further hampered by poor bioavailability and insufficient accumulation at fibrotic sites. To overcome these challenges, we developed a multifunctional nanotherapeutic platform, termed HPA@NPs, through co-assembly of hyaluronic acid-platycodin D (HA-PD) and aspirin-platycodin D (ASA-PD) conjugates. This nanosystem enables concurrent modulation of multiple PF-relevant pathological features. Physicochemical characterization showed that HPA@NPs possess uniform nanoscale size, low critical aggregation concentration, and excellent colloidal stability, supporting prolonged blood circulation. In vitro, HPA@NPs showed efficient cellular uptake consistent with their HA-based design and were accompanied by inhibition of EMT, fibroblast activation, and M2 macrophage polarization, together with reduced expression of IL-10 and Arg-1. In bleomycin-induced PF mice, HPA@NPs significantly improved pulmonary function and attenuated histopathological damage. At the molecular level, HPA@NPs down-regulated fibrosis-related markers (Col1a1, TGF-β1, α-SMA), while up-regulating the epithelial tight-junction protein ZO-1 and down-regulating mesenchymal markers (N-cadherin, vimentin), confirming effective reversal of EMT. The therapeutic outcome of HPA@NPs surpassed that of monotherapy, highlighting a synergistic anti-fibrotic effect. Importantly, HPA@NPs exhibited no detectable cytotoxicity, hemolytic activity, or major organ toxicity at therapeutic doses, demonstrating favorable biocompatibility. In summary, HPA@NPs integrate precise targeting, multi-pathway synergy, and excellent biosafety, offering a promising translational strategy for PF treatment.