Journal
NANO LETTERS
Volume 22, Issue 17, Pages 6877-6887Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.nanolett.2c01005
Keywords
Cancer Radiotherapy; Extracellular Matrix; Transcytosis; Programmed Self-assembly; Pancreatic Adenocarcinoma
Categories
Funding
- National Key R&D Program of China [2020YFA0710700]
- National Natural Science Foundation of China [52025036, 32101139, 52103192, 82000018]
- Fundamental Research Fund for the Central Universities [WK9100000006, WK9100000003, WK2480000006, WK9110000174]
- China Postdoctoral Science Foundation [2020M683160]
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This study discovered that the pyknomorphic extracellular matrix (ECM) acts as a barrier to impede the active transcytosis of nanoparticles in tumors. However, degradation of the ECM's pivotal constituent, collagen, effectively enhances intracellular transcytosis. Specifically, a collagenase conjugating transcytosis nanoparticle (Col-TNP) can dissociate into collagenase and cationized gold nanoparticles in the tumor's acidic environment, enabling their ECM tampering ability and active transcytosis in tumors.
Intracellular transcytosis can enhance the penetration of nanomedicines to deep avascular tumor tissues, but strategies that can improve transcytosis are limited. In this study, we discovered that pyknomorphic extracellular matrix (ECM) is a shield that impairs endocytosis of nanoparticles and their movement between adjacent cells and thus limits their active transcytosis in tumors. We further showed that degradation of pivotal constituent of ECM (i.e., collagen) effectively enhances intracellular transcytosis of nanoparticles. Specifically, a collagenase conjugating transcytosis nanoparticle (Col-TNP) can dissociate into collagenase and cationized gold nanoparticles in response to tumor acidity, which enables their ECM tampering ability and active transcytosis in tumors. The breakage of ECM further enhances the active transcytosis of cationized nanoparticles into deep tumor tissues as well as radiosensitization efficacy of pancreatic adenocarcinoma. Our study opens up new paths to enhance the active transcytosis of nanomedicines for the treatment of cancers and other diseases.
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