Efficacy of umbelliferone-loaded nanostructured lipid carrier in the management of bleomycin-induced idiopathic pulmonary fibrosis: experimental and network pharmacology insight

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive lung disorder with an average survival rate of 3 to 5 years. IPF presents a significant challenge in clinical management, necessitating novel therapeutic approaches. Nanostructured lipid carriers (NLCs) have proven to be promising vehicles for targeted drug delivery to the lung tissues. This research focuses on formulating and evaluating umbelliferone (UMB)-loaded NLCs for the treatment of IPF. UMB-NLC was formulated using the hot emulsion ultrasonication method and was characterized. The formulation was then tested for its efficacy in a bleomycin-induced IPF mice model. Leukocyte infiltration and interleukin-6 were estimated in the bronchoalveolar lavage fluid (BALF). Various antioxidant activities were also assessed for the formulation, followed by histopathological analysis. Furthermore, an in silico mechanistic approach using network pharmacology was carried out to obtain genes of interest. Particle size analysis revealed a mean size of 174.9 ± 3.66 nm for UMB-NLC, ideal for lung tissue targeting. Zeta potential measurements indicated good stability (-34.3 ± 1.35 mV) for long-term storage. Fourier transform infrared spectroscopy (FTIR) confirmed the successful encapsulation of UMB within the lipid matrix of NLCs. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) demonstrated the amorphous state of UMB-NLC, indicating enhanced solubility and bioavailability. Field emission scanning electron microscopy (FESEM) revealed uniform, spherical particles in the nanometer range. Drug entrapment efficiency (EE%) and loading capacity (DL%) were found to be 85.03 ± 2.36% and 17.01 ± 0.48%, respectively, indicating efficient drug incorporation. In vitro release study showed uniform sustained drug release over 48 h, indicating the potential for prolonged therapeutic effect. In vivo studies using UMB-NLC demonstrated significant improvements in bleomycin-induced IPF. A restoration in body weight and lung/body-weight (L/B) ratio was observed compared to disease controls. BALF analysis revealed reduced leukocyte infiltration and decreased inflammatory cytokine IL-6 levels (**p < 0.01). Biochemical assays showed enhanced antioxidant status and reduced oxidative stress in lung tissues. Hydroxyproline content (HPO, **p < 0.01), malondialdehyde (MDA, ***p < 0.001), and total protein content (**p < 0.01) were significantly reduced, while glutathione (GSH, ***p < 0.001), superoxide dismutase (SOD, **p < 0.01), and catalase (CAT, **p < 0.01) were elevated. Histopathological analysis confirmed the attenuation of lung fibrosis with maintained alveolar architecture and reduced fibrotic deposition. Furthermore, network pharmacology identified UMB targets and IPF-related genes with a Venn diagram, and cytoHubba analysis revealed key hub genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment demonstrated UMB's involvement in IPF-related pathways, highlighting its therapeutic potential. Therefore, UMB-NLC may exhibit promising therapeutic potential in the treatment of IPF, offering targeted drug delivery, enhanced bioavailability, and improved efficacy in alleviating pulmonary inflammation and fibrosis.