{"paper_id":"91079cf7-3c31-4029-adcd-f7c82c72f63f","body_text":"Abstract\nEndometriosis progression is driven by oxidative stress and excessive angiogenesis within an inflammatory microenvironment. To overcome these challenges, we designed ROS/pH dual-responsive Alpelisib-loaded nanoparticles (Alp@TAT-AT7-NPs) functionalized with an anti-NRP1 peptide for targeted therapy. The nanoparticles exhibited superior stability, responsive drug release, and selective internalization by NRP1-overexpressing endothelial cells. In vitro results showed efficient inhibition of NRP1 and downstream PI3K/AKT signaling, along with decreased reactive oxygen species (ROS) and enhanced antioxidant enzyme activities. In an endometriosis rat model, treatment with Alp@TAT-AT7-NPs significantly reduced ectopic lesion burden and angiogenic markers (VEGF, CD34), while suppressing systemic inflammation and oxidative injury indicators such as IL-6, TNF-α, and MDA. Fluorescence imaging confirmed preferential accumulation of nanoparticles in CD31⁺ vascular regions. Mechanistic studies demonstrated that modulation of the Sema3A-NRP1-PI3K/AKT signaling axis restored redox homeostasis and inhibited pathological angiogenesis. These findings identify Alp@TAT-AT7-NPs as a synergistic nanoplatform that integrates microenvironment responsiveness with NRP1-targeted intervention, providing a promising therapeutic strategy for endometriosis.\nGraphical abstract\nSimilar content being viewed by others\nAbbreviations\n- AKT:\n-\nProtein Kinase B\n- ALT:\n-\nAlanine Aminotransferase\n- AST:\n-\nAspartate Aminotransferase\n- BSA:\n-\nBovine Serum Albumin\n- BUN:\n-\nBlood Urea Nitrogen\n- CAT:\n-\nCatalase\n- CCK-8:\n-\nCell Counting Kit-8\n- CD31:\n-\nCluster of Differentiation 31\n- Co-IP/MS:\n-\nCo-Immunoprecipitation and Mass Spectrometry\n- CREA:\n-\nCreatinine\n- DHE:\n-\nDihydroethidium\n- DEGs:\n-\nDifferentially Expressed Genes\n- DLS:\n-\nDynamic Light Scattering\n- DL:\n-\nDrug Loading\n- EcEM:\n-\nEctopic Endometriotic Lesions\n- EE:\n-\nEncapsulation Efficiency\n- ELISA:\n-\nEnzyme-Linked Immunosorbent Assay\n- EMS:\n-\nEndometriosis\n- FBS:\n-\nFetal Bovine Serum\n- FI:\n-\nFluorescence Intensity\n- FDR:\n-\nFalse Discovery Rate\n- GO:\n-\nGene Ontology\n- GSH:\n-\nGlutathione\n- H&E:\n-\nHematoxylin and Eosin\n- HPLC:\n-\nHigh-Performance Liquid Chromatography\n- HUVEC:\n-\nHuman Umbilical Vein Endothelial Cell\n- IHC:\n-\nImmunohistochemistry\n- IL-6:\n-\nInterleukin-6\n- IOD:\n-\nIntegrated Optical Density\n- KEGG:\n-\nKyoto Encyclopedia of Genes and Genomes\n- MDA:\n-\nMalondialdehyde\n- NAC:\n-\nN-Acetylcysteine\n- NPs:\n-\nNanoparticles\n- NRP1:\n-\nNeuropilin-1\n- PCA:\n-\nPrincipal Component Analysis\n- PBS:\n-\nPhosphate-Buffered Saline\n- PI3K:\n-\nPhosphatidylinositol-3-Kinase\n- PLA:\n-\nProximity Ligation Assay\n- ROS:\n-\nReactive Oxygen Species\n- RBCs:\n-\nRed Blood Cells\n- RU:\n-\nResonance Units\n- scRNA-seq:\n-\nSingle-Cell RNA Sequencing\n- SD:\n-\nSprague-Dawley\n- Sema3A:\n-\nSemaphorin 3 A\n- SOD:\n-\nSuperoxide Dismutase\n- SPR:\n-\nSurface Plasmon Resonance\n- TNF-α:\n-\nTumor Necrosis Factor-α\n- TEM:\n-\nTransmission Electron Microscopy\n- UAECs:\n-\nUterine Artery Endothelial Cells\n- VEGF:\n-\nVascular Endothelial Growth Factor\nAcknowledgements\nNone.\nFunding\nThis study was supported by the Suzhou Industrial Technology Innovation Project (No. SKY2023158), the Scientific Research Project of Jiangsu Provincial Health Commission (No. K2023025), the Suzhou Research on Collaborative Innovation of Medical-Engineering Integration (No. SZM2022008), the Jiangsu Province Association of Maternal and Child Health Projects (No. FYX202002), and the National Mentorship Training Program for Young Professionals in Suzhou City (No. Qngg2024015).\nAuthor information\nAuthors and Affiliations\nCorresponding authors\nEthics declarations\nEthics approval and consent to participate\nAll animal experiments were approved by the Animal Ethics Committee of Soochow University (No. 202508A0091).\nConsent for Publication\nNot applicable.\nCompeting interests\nThe authors declare no competing interests.\nAdditional information\nPublisher’s note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nElectronic Supplementary Material\nBelow is the link to the electronic supplementary material.\nRights and permissions\nOpen Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.\nAbout this article\nCite this article\nZhang, J., Zhang, H., Liu, W. et al. Anti-NRP1 peptide-engineered ROS/pH dual-responsive nanoparticles for Alpelisib delivery regulate Sema3A-NRP1/PI3K-AKT signaling to balance oxidative stress and inhibit angiogenesis in endometriosis. J Nanobiotechnol (2026). https://doi.org/10.1186/s12951-026-04560-6\nReceived:\nAccepted:\nPublished:\nDOI: https://doi.org/10.1186/s12951-026-04560-6","source_license":"CC0","license_restricted":false}