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

Nature Nanotechnology volume 19, pages 95–105 (2024)Cite this article

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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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Fig. 1: NPs form subendothelial pools at endothelial junctions in tumours.
Fig. 2: The BM accounts for the formation of NP pools and prevents NP extravasation.
Fig. 3: LHT promotes the formation of more NP pools by opening adherens junctional gaps.
Fig. 4: LHT-induced pool eruption releases the trapped NPs into the tumour interstitial space.
Fig. 5: Transmigrating neutrophils open the tumour BM barrier and induce pool eruption.
Fig. 6: Neutrophils rely on activated platelets to help find the pool sites.

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Data availability

All data supporting the findings of this study are presented graphically or in tables in the Article and Supplementary Information; all additional data are available as tabulated values from the corresponding author upon reasonable request. Source data are provided with this paper.

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Acknowledgements

This work was supported by grants from the National Key R&D Program of China (2020YFA0710700 to Y.W. and 2022YFC2303700 to W.J.), National Natural Science Foundation of China (52025036 to Y.W. and 52273156 to W.J.), Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0490000 to Y.W.) and Project of Collaborative Innovation for Colleges of Anhui Province (GXXT-2022-060 to W.J.). This work was partially carried out at the USTC Center for Micro and Nanoscale Research and Fabrication.

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Author notes

  1. These authors contributed equally: Qin Wang, Qirui Liang.

Authors and 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

    Qin Wang, Qirui Liang, Jiaxiang Dou, Han Zhou, Cici Zeng, Huimin Pan, Yanqiong Shen, Yi Liu, Wei Jiang & Yucai Wang

  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

    Qin Wang, Qirui Liang, Jiaxiang Dou, Han Zhou, Cici Zeng, Huimin Pan, Yanqiong Shen, Yi Liu, Wei Jiang & Yucai Wang

  3. Guangzhou Women and Children’s Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China

    Quan Li

  4. Department of Chemical and Biomolecular Engineering, College of Design and Engineering, National University of Singapore, Singapore, Singapore

    David Tai Leong

  5. Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China

    Yucai Wang

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Contributions

Q.W., Q. Liang and W.J. designed and performed the experiments. Q.W., Q. Liang and Y.W. analysed the experimental data. J.D. established tumour models. J.D., H.Z., C.Z., H.P. and Y.S. helped with animal experiments. W.J. designed and synthesized the polymers. Y.L. synthesized CPT–BFL. Q. Li provided the patient samples. Y.W., W.J., Q.W., Q. Liang and D.T.L. wrote the manuscript. Y.W. supervised the project, and all authors reviewed and edited the manuscript before submission.

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Correspondence to David Tai Leong, Wei Jiang or Yucai Wang.

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Nature Nanotechnology thanks Evi Stavrou, Horacio Cabral and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended Data Fig. 1 The basement membrane (BM) acts as a physiological barrier to prevent nanoparticle (NP) extravasation, and breaking through the barriers by a local hyperthermia therapy (LHT)-induced cooperative immune-driven strategy improves nanotherapeutic delivery into tumours.

a, Schematic showing that the BM contributes an additional mechanical barrier to restrict NPs in a subendothelial void (defined as the NP pool), preventing the passage of nanotherapeutic to access the tumour interstitial space. b, Schematic showing that neutrophil diapedesis induced by LHT treatment breaks the BM barrier and promotes NP pool eruption, leading to enhanced delivery of NPs into tumours. #1 LHT treatment opens endothelial junction gaps by degradation of VE-cadherin and promotes the formation of more NP pools. #2a The LHT-mediated inflammatory response recruits abundant activated platelets into NP pools. #2b Activated platelets combine with neutrophils to form platelet–neutrophil complexes and convoy neutrophils into tumours. #3 Activated platelets act as recruitment beacons to guide the neutrophils to the NP pool locations. #4 The neutrophils open BM barriers during diapedesis to liberate the entrapped NPs in pools through a repeatable series of vigorous explosive eruptions that culminates in deep and effective penetration of the NPs into the tumours.

Extended Data Fig. 2 LHT improved the delivery and therapeutic effect of clinical nanomedicines.

a, Fluorescent images of mice bearing bilateral orthotropic 4T1 tumours (n = 5 biologically independent samples). b, The accumulated amount of NPs in orthotropic tumours 24 h after injection of NPs (n = 5 biologically independent samples). c, Pseudocolor fluorescence images and corresponding intensity of NPs in LHT-treated tumour sections at different depths (n = 3 biologically independent samples). The results are normalized and shown as a heatmap. d, Fluorescent reflectance imaging of Lipo DOX ( ~ 75 nm) in orthotopic 4T1 tumours. e, Tumoral accumulation of Lipo DOX (n = 4 biologically independent samples). f, Fluorescent images of bilateral 4T1 tumour-bearing mice after control and LXY2 peptide treatments. g, Relative NP accumulation in LHT-treated tumours of mice with or without LXY2 peptide treatment (n = 3 biologically independent samples). h, Therapeutic schedule for bilateral 4T1-Luc tumour-bearing mice. Mice received α-Ly6G and LHT on tumours, followed by i.v. injection of MXT or Lipo MXT (4 mg kg–1). i, Tumour growth curves of mice after different treatments (n = 5 biologically independent samples). P < 1 × 10-15 in Lipo MXT group. j, Therapeutic schedule of bilateral orthotropic 4T1 tumour bearing mice. Mice received LXY2 peptide and LHT, followed by i.v. injection of Lipo DOX (5 mg kg–1). k, Tumour growth curves during the treatments (n = 5 biologically independent samples). P = 7.8 × 10-9 in Lipo DOX group. l, Tumour weight ratios for LHT-treated versus untreated tumours on the same mouse (n = 5 biologically independent samples). P = 3.4 × 10-6 between control and Lipo DOX; P = 5.0 × 10-6 between Lipo DOX and Lipo DOX plus LXY2 peptide. Data in e, g, i, k, and l are presented as mean ± s.d. Significant differences were assessed using a two-tailed unpaired Student’s t-test (b, e, g), a two-way ANOVA with Sidak’s multiple comparisons test (i, k), or a one-way ANOVA with Tukey’s multiple comparison test (l). NS, not significant.

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Supplementary information

Supplementary Information

Supplementary Methods, Figs. 1–60, Table 1 and unprocessed blots and gels for Supplementary Figures.

Reporting Summary

Supplementary Video 1

The process of NP pool formation in LHT-treated 4T1 tumours. The NP pool rapidly appeared in the subendothelial space with sustained spikes in fluorescent intensity, and was generally completed within 10 min in the LHT-treated tumours. The video shows the representative field recorded immediately after LHT treatment; the initial formation of the NP pool is defined as 0 min (exact time duration, min). NP pools were captured using a Nikon Ti2 confocal laser scanning microscope system every 0.5 min. NPs are in green.

Supplementary Video 2

Multiple eruptions occurred at the same NP pool site in LHT-treated tumours. Three consecutive on–off pool eruptions with different eruption intensities occurred within 60 min in LHT-treated tumours. The initiation of the eruption is defined as 0 min (exact time duration, min:s). Multiple pool eruption was captured using a Nikon Ti2 confocal laser scanning microscope system every 0.5 min. The normalized intensity of NPs is denoted by pseudocolour.

Supplementary Video 3

The process of neutrophil-triggered pool eruption during diapedesis. Neutrophils were labelled with phycoerythrin–Ly6G antibody. A well defined neutrophil cascade event was observed, including neutrophil capture and rolling, firm adhesion, crawling into the site of NP pools, the instant when neutrophils are breaking through the NP pools coinciding spatiotemporally with the pool eruption, and finally transmigration further into the tumour interstitial space. The initiation of pool eruption is defined as 0 min (exact time duration, min). Neutrophil diapedesis-induced pool eruption was captured using a Nikon Ti2 confocal laser scanning microscope system every 1 min. NPs are in green and neutrophils are in purple.

Supplementary Video 4

The recruitment process of platelets into the NP pool in LHT-treated 4T1 tumours. A fluorescent-labelled anti-mouse CD49b antibody was used to tag platelets. In the early phase of pool formation, platelets were quickly recruited and aggregated into the NP pools within 20 min. The video depicts time points occurring after LHT (the exact time duration, min). Platelet recruitment was captured using a Nikon Ti2 confocal laser scanning microscope system every 1 min. NPs are in green and platelets are in purple.

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Wang, Q., Liang, Q., Dou, J. et al. Breaking through the basement membrane barrier to improve nanotherapeutic delivery to tumours. Nat. Nanotechnol. 19, 95–105 (2024). https://doi.org/10.1038/s41565-023-01498-w

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