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Steric stabilization-independent stealth cloak enables nanoreactors-mediated starvation therapy against refractory cancer

Nature Biomedical Engineering (2025)Cite this article

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An Author Correction to this article was published on 26 November 2025

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Abstract

The high interfacial energy of nanomaterials limits their certain biomedical applications that require stealthiness to minimize non-specific interaction with biological components. While steric repulsion-based entropic stabilization—such as PEGylation—has long been the dominant strategy for designing stealth nanomaterials, its inherent softness and susceptibility to dynamic deformation and external forces often result in only moderate stealth performance. Here we report a distinct approach to achieving stealthiness by harnessing an ion-pair network, rather than maximizing steric repulsion. Using model polyion complex nanoparticles composed of equimolar charge ratios of polycations and polyanions, we demonstrate that increasing crosslinks between the constituent polyions beyond a critical threshold effectively reduces protein adsorption and macrophage uptake, enabling prolonged circulation with a half-life exceeding 100 hours. Building on this, we develop an asparaginase-loaded vesicular nanoreactor enveloped by a semi-permeable ion-pair network sheath for asparagine starvation therapy. The extended circulation of these nanoreactors enables sustained depletion of asparagine, leading to improved therapeutic outcomes for metastatic breast and pancreatic cancers. Our findings open an avenue for improving the pharmacokinetics of nanomaterials for therapeutic delivery through delicately engineering stable intermolecular structures with holistic cooperativity.

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Fig. 1: In vitro macrophage uptake and protein binding of PIC nanoparticles.
Fig. 2: Extended circulation behaviour of PIC nanoparticles.
Fig. 3: The stability of the ion-pair network.
Fig. 4: Proposed percolative ion-pair network and charge neutralization mechanism.
Fig. 5: In vivo nano–bio interaction of short-circulating nanoparticles.
Fig. 6: In vivo clearance of long-circulating nanoparticles.
Fig. 7: Therapeutic efficacy of asparaginase-loaded vesicular nanoreactor (ASNase@V) in metastatic breast cancer.
Fig. 8: Alleviation of desmoplasia by ASNase@V in pancreatic cancer and therapeutic efficacy in combination with immunotherapy.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information files. All data generated in this study, including source data for the figures, are available from the corresponding authors upon reasonable request. Source data are provided with this paper.

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Acknowledgements

This research was supported financially by the Japan Science and Technology Agency (JST) through the Center of Innovation (COI) Program (JPMJCE1305 to K.K.) and the Open Innovation Platform for Industry-Academia Co-creation (COI-NEXT) Program (JPMJPF2202 to H.K. and K.K.), Grants-in-Aid for Early-Career Scientist (20K20209 to J.L.) and Scientific Research (B) (23H03740 to J.L.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT)/the Japan Society for the Promotion of Science (JSPS), and the JSPS International Research Fellowship (J.L., P17356; K.K. as the host researcher). This work was partially supported by Grants-in-Aid for Scientific Research (19H05720 and 22H00591 to M.T., 24K21109 to P.W.) from MEXT/JSPS and a grant for young researchers from the Hirose Foundation.

Author information

Author notes

  1. Kazuko Toh

    Present address: NucleoTIDE and PepTIDE Drug Discovery Center (TIDE), Institute of Biomedical Engineering, Institute of Science Tokyo, Tokyo, Japan

  2. Joachim F. R. Van Guyse

    Present address: Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands

  3. Saed Abbasi

    Present address: Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

  4. Yasutaka Anraku

    Present address: Department of Materials Science and Engineering, School of Materials and Chemical Technology, Institute of Science Tokyo, Tokyo, Japan

  5. Yuki Mochida

    Present address: Department of Advanced Nanomedical Engineering, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan

Authors and Affiliations

  1. Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Japan

    Junjie Li, Kazuko Toh, Panyue Wen, Xueying Liu, Anjaneyulu Dirisala, Haochen Guo, Joachim F. R. Van Guyse, Saed Abbasi, Yasutaka Anraku, Yuki Mochida, Hiroaki Kinoh & Kazunori Kataoka

  2. Institute for Materials Chemistry and Engineering, Kyushu University, Fukuoka, Japan

    Junjie Li, Panyue Wen & Masaru Tanaka

  3. Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan

    Horacio Cabral

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Contributions

J.L. and K.K. conceived of the ideas. J.L. designed and performed the experiments and analysed the data. J.L. prepared the figures and wrote the paper with input from all authors. P.W. helped with the preparation of PIC nanoparticles and in vitro investigation. K.T. and J.L. independently repeated intravital microscopic observation. J.F.R.V.G. helped with the NMR spectroscopic characterization. X.L. helped with the collection of blood and organs and the evaluation of antitumour efficacy. A.D., P.W., H.G. and H.C. contributed to the evaluation and discussion of biodistribution. Y.M. contributed to the inductively coupled plasma mass spectroscopy measurements. S.A. helped with the preparation of liposomes. H.K. helped with the flow cytometry measurements. Y.M. and Y.A. supplied some polymers. M.T. contributed to the discussion on the hydration effect. K.K. commented on the paper. J.L. and K.K. revised the paper. K.K. and J.L. supervised the project.

Corresponding authors

Correspondence to Junjie Li or Kazunori Kataoka.

Ethics declarations

Competing interests

The patent application (PCT/JP2023/37954) related to this work has been filed (J.L. and K.K.). The other authors declare no competing interests.

Peer review

Peer review information

Nature Biomedical Engineering thanks Martina Stenzel 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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Supplementary information

Supplementary Information

Supplementary Figs. 1–37, Table 1 and legends for Videos 1–6.

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Supplementary Video 1

Schematic illustration demonstrating the correlation between the stability of the ion-pair network sheath and nano–bio interactions.

Supplementary Video 2

IVRTCLSM imaging of blood vessels in the mouse ear dermis after injection of Cy5-labelled dePEGylated vesicles with 32.6% crosslinking (red).

Supplementary Video 3

IVRTCLSM imaging of the bloodstream FRET profile of Cy3/Cy5-co-labelled M39.5% nanoparticles in mouse ear dermis blood vessels. Stable FRET signal is demonstrated by a consistent Cy5/Cy3 ratio (yellow) in the imaging.

Supplementary Video 4

IVRTCLSM imaging of liver tissue after injection of Cy5-labelled dePEGylated vesicles with 32.6% crosslinking (red). The green fluorescence represents auto-fluorescence from liver parenchyma.

Supplementary Video 5

IVRTCLSM imaging of liver tissue after injection of Cy5-labelled M39.5% nanoparticles (red).

Supplementary Video 6

IVRTCLSM imaging of liver tissue after injection of Cy5-labelled V30.3% nanoparticles (red).

Supplementary Data

Source data for figures in the Supplementary Information.

Source data

Source Data Figs. 1–8

Statistical source data for Figs. 1–8.

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Li, J., Toh, K., Wen, P. et al. Steric stabilization-independent stealth cloak enables nanoreactors-mediated starvation therapy against refractory cancer. Nat. Biomed. Eng (2025). https://doi.org/10.1038/s41551-025-01534-1

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