The central dogma that nanoparticle delivery to tumours requires enhanced leakiness of vasculatures is a topic of debate. To address this, we propose a single-vessel quantitative analysis method by taking advantage of protein-based nanoprobes and image-segmentation-based machine learning (nano-ISML). Using nano-ISML, >67,000 individual blood vessels from 32 tumour models were quantified, revealing highly heterogenous vascular permeability of protein-based nanoparticles. There was a >13-fold difference in the percentage of high-permeability vessels in different tumours and >100-fold penetration ability in vessels with the highest permeability compared with vessels with the lowest permeability. Our data suggest passive extravasation and transendothelial transport were the dominant mechanisms for high- and low-permeability tumour vessels, respectively. To exemplify the nano-ISML-assisted rational design of nanomedicines, genetically tailored protein nanoparticles with improved transendothelial transport in low-permeability tumours were developed. Our study delineates the heterogeneity of tumour vascular permeability and defines a direction for the rational design of next-generation anticancer nanomedicines.
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The authors declare that data supporting the findings of this study are available within the article and its Supplementary Information. All relevant data can be made available upon reasonable request to the corresponding authors. Source data are provided with this paper.
The source code of machine learning-based model can be accessed at https://github.com/balabilibili24/Confocal_images_analysis.git.
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This work was supported by the National Natural Science Foundation of China 91959129 (X.H.), 32271448 (X.H.), 82072054 (J.Z.), 31870999 (X.H.), the National Key Research and Development Program of China 2022YFA1105100 (X.H.), Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project TSBICIP-KJGG-014-03 (X.H.) and the Nankai University Hundred Young Academic Leaders Program.
The authors declare no competing interests.
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Zhu, M., Zhuang, J., Li, Z. et al. Machine-learning-assisted single-vessel analysis of nanoparticle permeability in tumour vasculatures. Nat. Nanotechnol. (2023). https://doi.org/10.1038/s41565-023-01323-4