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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年10月31日

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  • 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,
  • Horacio Cabral,
  • Masaru Tanaka,
  • Kazunori Kataoka

摘要

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.