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Dual asparagine-depriving nanoparticles against solid tumors.

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This study introduces novel nanoparticles that sequentially deplete extracellular asparagine (Asn) and block its intracellular production, effectively treating solid tumors like breast and colorectal cancer in mice.

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Area of Science:

  • Biomedical Engineering
  • Cancer Therapy
  • Nanotechnology

Background:

  • Solid tumors resist L-asparaginase (ASNase) therapy due to active asparagine (Asn) biosynthesis.
  • Current treatments are limited for solid tumors unresponsive to traditional amino acid depletion.

Purpose of the Study:

  • To develop core-shell nanoparticles for sequential modulation of exogenous Asn supply and endogenous Asn production.
  • To overcome resistance of solid tumors to amino acid depletion therapy.

Main Methods:

  • Designed cascade-responsive nanoparticles (NPs) with reactive oxygen species-sensitive shells and acid-labile cores.
  • NPs sequentially release ASNase to scavenge extracellular Asn and rotenone to inhibit intracellular Asn biosynthesis.
  • Tested NPs in murine models of triple-negative breast cancer and colorectal cancer.

Main Results:

  • NPs significantly suppressed primary and relapsed tumor growth and epithelial-mesenchymal transition.
  • Achieved complete eradication of spontaneous and post-surgical metastasis.
  • Conferred long-term T cell memory resistance to tumor rechallenge.

Conclusions:

  • This dual Asn-depriving nanoparticle strategy effectively treats solid tumors.
  • Represents a generalized approach for amino acid depletion therapy against solid tumors.
  • Demonstrates potential for overcoming therapeutic resistance in cancer.