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

Jie Zhang, Zhang J, Zhang H, Hong Zhang, Haitao Zhang, Wei Liu, Liu W, Zhang Y, Yi Zhang, Hou W, Wenjie Hou, Chi C, Chi Chi
Journal of nanobiotechnology · 2026 · vol. 24(1) · doi:10.1186/s12951-026-04560-6 · PMID:42251335 · PMC13471664 · W7163737881
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Engineered ROS/pH dual-responsive, anti-NRP1 peptide nanoparticles delivered Alpelisib to inhibit Sema3A-NRP1/PI3K-AKT signaling, balancing oxidative stress and angiogenesis in endometriosis.

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The paper studied ROS/pH dual-responsive, anti-NRP1 peptide functionalized nanoparticles designed to deliver alpelisib and target the Sema3A–NRP1–PI3K/AKT signaling axis, aiming to reduce oxidative stress and angiogenesis in an endometriosis context. Using in vitro experiments in NRP1-overexpressing endothelial cells and an endometriosis rat model, the authors found that the nanoparticles were stable, released drug in response to ROS/pH cues, showed selective endothelial uptake, inhibited NRP1 and PI3K/AKT signaling, decreased reactive oxygen species while increasing antioxidant enzyme activities, and reduced ectopic lesion burden and angiogenic markers (VEGF, CD34) with lower IL-6, TNF-α, and MDA. They also reported mechanistic evidence that modulation of the Sema3A-NRP1-PI3K/AKT axis restored redox homeostasis and suppressed pathological angiogenesis, with fluorescence imaging showing preferential accumulation in CD31+ vascular regions. The study explicitly focuses on in vitro and rat-model outcomes without stating additional human validation limitations. This paper is centrally about endometriosis—engineering anti-NRP1 ROS/pH-responsive alpelisib nanoparticles to inhibit endometriosis-associated oxidative stress and angiogenesis via Sema3A–NRP1–PI3K/AKT signaling.

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Abstract

Endometriosis 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.
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Abstract

Endometriosis 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. Graphical abstract Similar content being viewed by others Abbreviations - AKT: - Protein Kinase B - ALT: - Alanine Aminotransferase - AST: - Aspartate Aminotransferase - BSA: - Bovine Serum Albumin - BUN: - Blood Urea Nitrogen - CAT: - Catalase - CCK-8: - Cell Counting Kit-8 - CD31: - Cluster of Differentiation 31 - Co-IP/MS: - Co-Immunoprecipitation and Mass Spectrometry - CREA: - Creatinine - DHE: - Dihydroethidium - DEGs: - Differentially Expressed Genes - DLS: - Dynamic Light Scattering - DL: - Drug Loading - EcEM: - Ectopic Endometriotic Lesions - EE: - Encapsulation Efficiency - ELISA: - Enzyme-Linked Immunosorbent Assay - EMS: - Endometriosis - FBS: - Fetal Bovine Serum - FI: - Fluorescence Intensity - FDR: - False Discovery Rate - GO: - Gene Ontology - GSH: - Glutathione - H&E: - Hematoxylin and Eosin - HPLC: - High-Performance Liquid Chromatography - HUVEC: - Human Umbilical Vein Endothelial Cell - IHC: - Immunohistochemistry - IL-6: - Interleukin-6 - IOD: - Integrated Optical Density - KEGG: - Kyoto Encyclopedia of Genes and Genomes - MDA: - Malondialdehyde - NAC: - N-Acetylcysteine - NPs: - Nanoparticles - NRP1: - Neuropilin-1 - PCA: - Principal Component Analysis - PBS: - Phosphate-Buffered Saline - PI3K: - Phosphatidylinositol-3-Kinase - PLA: - Proximity Ligation Assay - ROS: - Reactive Oxygen Species - RBCs: - Red Blood Cells - RU: - Resonance Units - scRNA-seq: - Single-Cell RNA Sequencing - SD: - Sprague-Dawley - Sema3A: - Semaphorin 3 A - SOD: - Superoxide Dismutase - SPR: - Surface Plasmon Resonance - TNF-α: - Tumor Necrosis Factor-α - TEM: - Transmission Electron Microscopy - UAECs: - Uterine Artery Endothelial Cells - VEGF: - Vascular Endothelial Growth Factor

Acknowledgements

None. Funding This 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). Author information Authors and Affiliations Corresponding authors Ethics declarations Ethics approval and consent to participate All animal experiments were approved by the Animal Ethics Committee of Soochow University (No. 202508A0091). Consent for Publication Not applicable. Competing interests The authors declare no competing interests. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Electronic Supplementary Material Below is the link to the electronic supplementary material. Rights and permissions Open 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/. About this article Cite this article Zhang, 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 Received: Accepted: Published: DOI: https://doi.org/10.1186/s12951-026-04560-6

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MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis

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