Breaking through the basement membrane barrier to improve nanotherapeutic delivery to tumours

Nat Nanotechnol. 2024 Jan;19(1):95-105. doi: 10.1038/s41565-023-01498-w.

Qin Wang ^# ¹ ², Qirui Liang ^# ¹ ², Jiaxiang Dou ¹ ², Han Zhou ¹ ², Cici Zeng ¹ ², Huimin Pan ¹ ², Yanqiong Shen ¹ ², Quan Li ³, Yi Liu ¹ ², David Tai Leong ⁴, Wei Jiang ⁵ ⁶, Yucai Wang ⁷ ⁸ ⁹

Affiliations

1 Department of Radiology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
2 The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
3 Guangzhou Women and Children's Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China.
4 Department of Chemical and Biomolecular Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore. cheltwd@nus.edu.sg.
5 Department of Radiology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. jwustc@ustc.edu.cn.
6 The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. jwustc@ustc.edu.cn.
7 Department of Radiology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. yucaiwang@ustc.edu.cn.
8 The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. yucaiwang@ustc.edu.cn.
9 Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China. yucaiwang@ustc.edu.cn.
# Contributed equally.

PMID: 37709950 DOI: 10.1038/s41565-023-01498-w

Abstract

An effective nanotherapeutic transport from the vasculature to the tumour is crucial for Cancer treatment with minimal side effects. Here we demonstrate that, in addition to the endothelial barrier, the tumour vascular basement membrane surrounding the endothelium acts as a formidable mechanical barrier that entraps nanoparticles (NPs) in the subendothelial void, forming perivascular NP pools. Breaking through this basement membrane barrier substantially increases NP extravasation. Using inflammation triggered by local hyperthermia, we develop a cooperative immunodriven strategy to overcome the basement membrane barrier that leads to robust tumour killing. Hyperthermia-triggered accumulation and inflammation of platelets attract neutrophils to the NP pools. The subsequent movement of neutrophils through the basement membrane can release the NPs entrapped in the subendothelial void, resulting in increased NP penetration into deeper tumours. We show the necessity of considering the tumour vascular basement membrane barrier when delivering nanotherapeutics. Understanding this barrier will contribute to developing more effective antitumour therapies.

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HY-P10934

LXY3

VLA-3 Blocking Peptide

Integrin

Cancer

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