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Ethnopharmacological Relevance: Zangsiwei(ZSW) is a traditional Tibetan medicine from China consisting of extracts of Rhododendron anthopogonoides Maxim, Gentiana Tourn, Corydalis hendersonii Hemsl and Berberis kansuensis C.K.Schneid. Traditionally, ZSW has been used by Tibetan physicians to treat chronic respiratory diseases. The role of ZSW in particulate matter-induced lung inflammation and fibrosis remains unclear., Aim of the Study: Combining non-targeted metabolomics, network pharmacology, and molecular docking to explore the mechanism of ZSW in the treatment of particulate matter-induced lung inflammation and fibrosis, and validated by in vivo and in vitro experiments., Materials and Methods: The serum metabolite profile post-ZSW administration was first identified utilizing non-targeted metabolomics. Network pharmacology and molecular docking were employed to predict potential bioactive components and their corresponding targets. The in silico predictions were subsequently validated through in vivo studies in mice exposed to PM2.5 and silica dust, as well as in vitro studies utilizing human lung epithelial cells (A549) and lung fibroblasts (MRC5)., Results: Metabolomic analysis identified specific serum metabolites that were associated with ZSW treatment. Network pharmacology and molecular docking identified key targets involved in the Transforming growth factor-β (TGF-β)/SMAD pathway, which were subsequently validated through in vivo experiments demonstrating a reduction in lung inflammation and fibrosis in ZSW-treated mice. In vitro studies demonstrated that ZSW exerts protective effects against PM2.5-induced cytotoxicity and modulates fibrotic markers in a dose-dependent manner. This is consistent with the inhibition of the TGF-β/SMAD pathway., Conclusion: Our integrated approach, which combines non-targeted metabolomics, network pharmacology, and molecular docking, followed by rigorous in vivo and in vitro validation, establishes ZSW as a potential therapeutic agent for particulate matter-induced lung inflammation and fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Poor deep tumor penetration and incomplete intracellular drug release remain challenges for antitumor nanomedicine application in clinical settings. Herein, a nanomedicine (RLPA-NPs) is developed that can achieve prolonged blood circulation, deep tumor penetration, active-targeting of cancer cells, endosome/lysosome escape, and intracellular selectivity self-amplified drug release for effective drug delivery. The RLPA-NPs are constructed by encapsulation of a pH-sensitive polymer octadecylamine-poly(aspartate-1-(3-aminopropyl) imidazole) (OA-P(Asp-API)) and a ROS-generation agent, β-Lapachone (Lap), in micelles assembled by the tumor-penetration peptide internalizing RGD (iRGD)-modified ROS-responsive paclitaxel (PTX)-prodrug. iRGD could promote RLPA-NPs penetration into deep tumor tissue, and specific targeting to cancer cells. After internalization by cancer cells through receptor-mediated endocytosis, OA-P(Asp-API) can rapidly protonate in the endosome's acidic environment, resulting in RLPA-NPs escape from the endosome through the "proton sponge effect". At the same time, the RLPA-NPs micelle disassembles, releasing Lap and PTX-prodrug. Subsequently, the released Lap could generate ROS, consequently amplifying and accelerating PTX release to kill tumor cells. The in vitro and in vivo studies demonstrated that RLPA-NPs can significantly improve the therapeutic effect compared to control groups. Therefore, RLPA-NPs are a promising nanoplatform for overcoming multiple physiological and pathological barriers to enhance drug delivery., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)